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Sugano Y, Sekiya M, Murayama Y, Osaki Y, Iwasaki H, Suzuki H, Fukushima H, Suzuki H, Noguchi E, Shimano H. Case-based learning: a case of maturity-onset diabetes of the young 5 (MODY5) due to 17q12 microdeletion with a diminished plasma glucagon level. Diabetol Int 2025; 16:432-438. [PMID: 40166445 PMCID: PMC11954765 DOI: 10.1007/s13340-025-00804-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 02/04/2025] [Indexed: 04/02/2025]
Abstract
Maturity-onset diabetes of the young type 5 (MODY5), causally associated with loss-of-function of the HNF1B gene, is a rare form of monogenic diabetes that has been underdiagnosed in part because microdeletions of chromosome 17q12 encompassing the HNF1B gene cannot be detected by sequencing-based approaches, which accounts for about 50% of MODY5 cases. We herein describe a 37-year-old Japanese woman who manifested diabetic ketosis at the onset. The coexistence of features associated with MODY5, including abnormal renal function, impaired insulin secretion, pancreatic hypoplasia and hypomagnesemia, prompted us to decode her genomic information using whole-exome sequencing, where we were not able to identify any pathogenic HNF1B gene mutations. We further examined her genomic integrity using multiplex ligation probe amplification (MLPA) analysis, leading to identification of the 17q12 microdeletion which was further supported by array comparative genomic hybridization (array-CGH). Her insulin secretory capacity was insufficient, whereas her total daily dose of insulin was 11 U/day (0.25 U/Kg/day), indicating that she was relatively sensitive to insulin. As a possible explanation, we found that her plasma glucagon level was below the detection limit. Since inactivation of acetyl-CoA carboxylase 1 (ACACA), encoded in close proximity to the HNF1B gene, was reported to blunt glucagon secretion, the concurrent deletion of the ACACA gene may be in part responsible for this manifestation. In conclusion, the genetic analyses of MODY5 cases require the judicious use of appropriate genetic technologies. In addition, alpha-cell dysfunction may at least in part account for the variable clinical manifestations of MODY5. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-025-00804-2.
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Affiliation(s)
- Yoko Sugano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Motohiro Sekiya
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Yuki Murayama
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Yoshinori Osaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Hitoshi Iwasaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Hiroaki Suzuki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Hiroko Fukushima
- Department of Child Health, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Hisato Suzuki
- Department of Medical Genetics, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Emiko Noguchi
- Department of Medical Genetics, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
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Sue M, Watanabe M, Inoue A, Katayama A, Teshigawara S, Matsushita Y, Takeda M, Iseda I, Eguchi J, Hida K. Maturity-Onset Diabetes of the Young (MODY) With HNF1B p.Glu105Lys Mutation Achieving Significant Insulin Reduction on Tirzepatide: A Case Report. Clin Case Rep 2025; 13:e70173. [PMID: 39902194 PMCID: PMC11790339 DOI: 10.1002/ccr3.70173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/06/2025] [Accepted: 01/26/2025] [Indexed: 02/05/2025] Open
Abstract
This report describes the first case of maturity-onset diabetes in young (MODY) with HNF1B mutation started administration of the dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, tirzepatide. A 26-year-old female with a 15-year history of diabetes mellitus was diagnosed with MODY, which is characterized by decreased insulin secretion. She was treated with tirzepatide, which significantly improved her glycemic management; insulin secretion increased the fasting serum C-peptide immunoreactivity from 0.36 to 1.09 ng/mL. The patient discontinued glimepiride, and her total daily insulin dose was reduced from 88 to 4 units. This report highlights the glucose-lowering effects of tirzepatide in a patient with MODY who has the HNF1B p.Glu105Lys mutation.
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Affiliation(s)
- Mihiro Sue
- Department of Diabetology and MetabolismNHO Okayama Medical CenterOkayamaJapan
| | - Mayu Watanabe
- Department of Diabetology and MetabolismNHO Okayama Medical CenterOkayamaJapan
| | - Ayumi Inoue
- Department of Diabetology and MetabolismNHO Okayama Medical CenterOkayamaJapan
| | - Akihiro Katayama
- Department of Diabetology and MetabolismNHO Okayama Medical CenterOkayamaJapan
| | - Sanae Teshigawara
- Department of Internal Medicine, Diabetes CenterOkayama Saiseikai General HospitalOkayamaJapan
| | - Yuichi Matsushita
- Department of Diabetology and MetabolismNHO Okayama Medical CenterOkayamaJapan
| | - Masaya Takeda
- Department of Diabetology and MetabolismNHO Okayama Medical CenterOkayamaJapan
| | - Izumi Iseda
- Department of Diabetology and MetabolismNHO Okayama Medical CenterOkayamaJapan
| | - Jun Eguchi
- Department of Nephrology, Rheumatology, Endocrinology and MetabolismOkayama University Faculty of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan
| | - Kazuyuki Hida
- Department of Diabetology and MetabolismNHO Okayama Medical CenterOkayamaJapan
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Horikawa Y, Hosomichi K, Yabe D. Monogenic diabetes. Diabetol Int 2024; 15:679-687. [PMID: 39469542 PMCID: PMC11512936 DOI: 10.1007/s13340-024-00698-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 01/25/2024] [Indexed: 10/30/2024]
Abstract
Diseases in which genetic factors contribute to nearly 100% of the causation by single-gene mutations are referred to as monogenic disorders or Mendelian genetic diseases. These include neonatal diabetes mellitus (NDM), presenting within the first six months of life, maturity-onset diabetes of the young (MODY), developing later in childhood or adolescence, mitochondrial diabetes (MIDD), and insulin-resistant disorders, etc. On the other hand, common lifestyle-related diseases such as type 2 diabetes (T2DM), hypertension and dyslipidemia are multifactorial, emerging through complex interplay of genetic and environmental factors. The identification of causative genes for diabetes resulting from single-gene abnormalities not only unveils previously unknown mechanisms of insulin secretion and sensitivity at the molecular level but also reveals novel targets for drug development. Moreover, monogenic diabetes in which insulin secretion is impaired serve to clarify the pathophysiology and suggest therapeutic targets for the common multifactorial type 2 diabetes mellitus prevalent in the Japanese population, which is characterized by impaired insulin secretion. In this study, we characterize the various monogenic subtypes of diabetes so far identified.
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Affiliation(s)
- Yukio Horikawa
- Department of Diabetes, Endocrinology and Metabolism, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Japan
- Clinical Genetics Center, Gifu University Hospital, Gifu, Japan
- Center for Patient Flow Management, Gifu University Hospital, Gifu, Japan
| | - Kazuyoshi Hosomichi
- Laboratory of Computational Genomics, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392 Japan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Japan
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Osaka, 553-0003 Japan
- Center for One Medicine Innovative Translational Research, Gifu University, Gifu, 501-1194 Japan
- Center for Research, Education and Development for Healthcare Life Design, Gifu University, Gifu, 501-1194 Japan
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Takase K, Susa S, Sato H, Hada Y, Nagaoka K, Takakubo N, Karasawa S, Kameda W, Numakura C, Ishizawa K. Identification of causative gene variants for patients with known monogenic diabetes using a targeted next-generation sequencing panel in a single-center study. Diabetol Int 2024; 15:203-211. [PMID: 38524932 PMCID: PMC10959868 DOI: 10.1007/s13340-023-00669-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 10/19/2023] [Indexed: 03/26/2024]
Abstract
Aims We aimed to verify the usefulness of targeted next-generation sequencing (NGS) technology for diagnosing monogenic diabetes in a single center. Methods We designed an amplicon-based NGS panel targeting 34 genes associated with known monogenic diabetes and performed resequencing in 56 patients with autoantibody-negative diabetes mellitus diagnosed at < 50 years who had not been highly obese. By bioinformatic analysis, we filtered significant variants based on allele frequency (< 0.005 in East Asians) and functional prediction. We estimated the pathogenicity of each variant upon considering the family history. Results Overall, 16 candidate causative variants were identified in 16 patients. Among them, two previously known heterozygous nonsynonymous single-nucleotide variants associated with monogenic diabetes were confirmed as causative variants: one each in the GCK and WFS1 genes. The former was found in two independent diabetes-affected families. Two novel putatively deleterious heterozygous variants were also assumed to be causative from the family history: one frameshift and one nonsynonymous single-nucleotide variant in the HNF4A gene. Twelve variants remained as candidates associated with the development of diabetes. Conclusion Targeted NGS panel testing was useful to diagnose various forms of monogenic diabetes in combination with familial analysis, but additional ingenuity would be needed for practice. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-023-00669-3.
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Affiliation(s)
- Kaoru Takase
- Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan
| | - Shinji Susa
- Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan
| | - Hidenori Sato
- Genomic Information Analysis Unit, Department of Genomic Cohort Research, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan
| | - Yurika Hada
- Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan
| | - Kyoko Nagaoka
- Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan
| | - Noe Takakubo
- Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan
- Takakubo Clinic, 2-9-7 Kitamachi, Warabi, Saitama 335-0001 Japan
| | - Shigeru Karasawa
- Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan
| | - Wataru Kameda
- Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan
| | - Chikahiko Numakura
- Department of Pediatrics and Clinical Genomics, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Saitama 350-0495 Japan
| | - Kenichi Ishizawa
- Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan
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Hasegawa Y, Takahashi Y, Nagasawa K, Kinno H, Oda T, Hangai M, Odashima Y, Suzuki Y, Shimizu J, Ando T, Egawa I, Hashizume K, Nata K, Yabe D, Horikawa Y, Ishigaki Y. Japanese 17q12 Deletion Syndrome with Complex Clinical Manifestations. Intern Med 2024; 63:687-692. [PMID: 38432894 PMCID: PMC10982014 DOI: 10.2169/internalmedicine.1660-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 05/29/2023] [Indexed: 03/05/2024] Open
Abstract
17q12 deletion syndrome is a rare chromosomal anomaly with variable phenotypes, caused by the heterozygous deletion of chromosome 17q12. We herein report a 35-year-old Japanese patient with chromosomal 17q12 deletion syndrome identified by de novo deletion of the 1.46 Mb segment at the 17q12 band by genetic analyses. He exhibited a wide range of phenotypes, such as maturity-onset diabetes of the young (MODY) type 5, structural or functional abnormalities of the kidney, liver, and pancreas; facial dysmorphic features, electrolyte disorders; keratoconus, and acquired perforating dermatosis. This case report provides valuable resources concerning the clinical spectrum of rare 17q12 deletion syndrome.
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Affiliation(s)
- Yutaka Hasegawa
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yoshihiko Takahashi
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Kan Nagasawa
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Hirofumi Kinno
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Tomoyasu Oda
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Mari Hangai
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yoshimi Odashima
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yoko Suzuki
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Jun Shimizu
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Toshihiko Ando
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Isao Egawa
- Department of Ophthalmology, School of Medicine, Iwate Medical University, Japan
| | - Kouhei Hashizume
- Department of Ophthalmology, School of Medicine, Iwate Medical University, Japan
| | - Koji Nata
- Division of Medical Biochemistry, School of Pharmacy, Iwate Medical University, Japan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism/Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Japan
| | - Yukio Horikawa
- Department of Diabetes, Endocrinology and Metabolism/Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Japan
- Clinical Genetics Center, Gifu University Hospital, Japan
| | - Yasushi Ishigaki
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Japan
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Li M, Popovic N, Wang Y, Chen C, Polychronakos C. Incomplete penetrance and variable expressivity in monogenic diabetes; a challenge but also an opportunity. Rev Endocr Metab Disord 2023; 24:673-684. [PMID: 37165203 DOI: 10.1007/s11154-023-09809-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/01/2023] [Indexed: 05/12/2023]
Abstract
Monogenic Forms of Diabetes (MFD) account for about 3% of all diabetes, and their accurate diagnosis often results in life-changing therapeutic reassignment for the patients. Like other Mendelian diseases, reduced penetrance and variable expressivity are often seen in several different types of MFD, where symptoms develop only in a portion of the persons who carry the pathogenic variant or vary widely in symptom severity and age of onset. This complicates diagnosis and disease management in MFD. In addition to its clinical importance, knowledge of genetic modifiers that confer penetrance and expressivity variability opens possibilities to identify protective genetic variants which may help probe the mechanisms of more common forms of diabetes and shed light in new therapeutic strategies. In this review, we will mainly address penetrance and expressivity variation in different types of MFD, factors that confer such variations and opportunities that come with such knowledge. Related literature was searched in PubMed, Medline and Embase. Papers with publication year from 1974 to 2023 are included. Data are either sourced from literatures or from OMIM, Clinvar and 1000 genome browser.
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Affiliation(s)
- Meihang Li
- College of pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, Guangdong, China.
- Department of Emergency, Department of Endorinology, Maoming People's Hospital, 101 Weimin Road, Maoming, Guangdong, China.
- Montreal Children's Hospital and the Endocrine Genetics Laboratory, Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, China.
- MaiDa Gene Technology, Zhoushan, China.
| | - Natalija Popovic
- Montreal Children's Hospital and the Endocrine Genetics Laboratory, Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, China
| | - Ying Wang
- College of pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, Guangdong, China
| | - Chunbo Chen
- Department of Emergency, Department of Endorinology, Maoming People's Hospital, 101 Weimin Road, Maoming, Guangdong, China
- Department of Critical Care Medicine, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of South University of Science and Technology, Shenzhen, China
- Department of Intensive Care Unit of Cardiovascular Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Constantin Polychronakos
- Montreal Children's Hospital and the Endocrine Genetics Laboratory, Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, China
- MaiDa Gene Technology, Zhoushan, China
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Guzmán GE, Madariaga I, Vargas CJ, Galeano LB, Guerra MA, Nastasi JA. Identification of 17q12 microdeletion syndrome in a Latin American patient with maturity-onset diabetes of the young subtype 5: a case report. J Med Case Rep 2023; 17:152. [PMID: 37016461 PMCID: PMC10074670 DOI: 10.1186/s13256-023-03873-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 03/03/2023] [Indexed: 04/06/2023] Open
Abstract
BACKGROUND Maturity-onset diabetes of the young comprises a large group of autosomal inherited gene mutations. Maturity-onset diabetes of the young subtype 5 is caused by mutations in the HNF1B gene. This gene is expressed in the early phase of embryonic development in the pancreas, kidneys, liver, and genital tract; therefore, kidney or urinary tract malformations are associated with diabetes mellitus. The 17q12 deletion syndrome is a cause of maturity-onset diabetes of the young subtype 5 that should be considered. CASE PRESENTATION We present the case of a 35-year-old Hispanic female patient with a history of bicornuate uterus and polycystic renal disease that required kidney transplant. She had insulin-dependent diabetes, with her mother, maternal grandmother, and great-grandmother showing a similar clinical manifestation. Molecular analysis showed a deletion in chromosome 17q12 involving 15 genes, including HNF1B. Therefore, a diagnosis of deletion syndrome was made. CONCLUSIONS The 17q12 deletion syndrome represents a rare genetic syndrome that involves different genes, including HNF1B. Principally, it is characterized by the combination of genitourinary tract malformations and diabetes mellitus, similar to our patient.
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Affiliation(s)
- Guillermo Edinson Guzmán
- Departamento de Endocrinología, Fundación Valle del Lili, Calle 18 No. 122-135, 760032, Cali, Colombia
| | - Ithzayana Madariaga
- Facultad de Ciencias de la Salud, Universidad Icesi, Calle 18 No. 122-135, 760032, Cali, Colombia
| | - Carlos Julio Vargas
- Facultad de Ciencias de la Salud, Universidad Icesi, Calle 18 No. 122-135, 760032, Cali, Colombia
| | - Laura Ballen Galeano
- Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cra 98 No.18-49, 760032, Cali, Colombia
| | - Maria Angélica Guerra
- Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cra 98 No.18-49, 760032, Cali, Colombia.
| | - Jose Antonio Nastasi
- Departamento de Genética, Fundación Valle del Lili, Calle 18 No. 122-135, 760032, Cali, Colombia
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Ng N, Mijares Zamuner M, Siddique N, Kim J, Burke M, Byrne MM. Genotype-phenotype correlations and response to glucose lowering therapy in subjects with HNF1β associated diabetes. Acta Diabetol 2022; 59:83-93. [PMID: 34487217 DOI: 10.1007/s00592-021-01794-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/24/2021] [Indexed: 12/26/2022]
Abstract
AIMS Molecular defects of hepatic nuclear factor 1β (HNF1β) are associated with multiorgan disease (renal disease, pancreatic hypoplasia, and genital tract anomalies) in addition to diabetes. We examined the phenotypic features, insulin secretory response to glucose, and response to treatment in subjects with HNF1β-MODY (MODY 5). METHODS Twelve subjects with HNF1β-MODY were phenotyped in detail. A 2-h oral glucose tolerance test was performed to establish insulin secretory response with glucose, insulin and C-peptide measurements taken at baseline and 30 min intervals. Clinical follow-up occurred bi-annually. RESULTS Ten of 12 subjects had diabetes with mean age of onset of 30.2 ± 15.5 years, fasting glucose of 9.7 ± 4.6 mmol/L and HbA1c of 60.9 ± 17.1 mmol/mol (7.7 ± 1.6%). Renal and/or pancreatic morphological abnormalities were found in 9 subjects. Mean fasting C-peptide (0.5 ± 0.4 nmol/L) and AUC C-peptide (1.5 ± 1.0 nmol/L/120 min) were reduced in our cohort with 4 subjects demonstrating marked insulin deficiency. OGIS was reduced at 290.2 ± 67.0 ml min-1 m-2. 6/10 subjects were on insulin therapy at initial diagnosis and 8/10 at last clinical follow-up. Mean insulin dose at last clinical follow-up was 0.45 ± 0.23units/kg/day. 5 subjects on insulin were trialled on sulphonylurea therapy, and none was successfully weaned off insulin. CONCLUSIONS Diagnosing HNF1β-MODY in a diabetes clinic is challenging due to its variable phenotype and variable age of onset. β-Cell dysfunction and insulin resistance contribute to diabetes in HNF1β-MODY. No subjects successfully transitioned to sulphonylurea. Early initiation of insulin therapy would be suitable to achieve glycaemic control. This emphasizes the importance of genetic testing for monogenic forms of diabetes to guide personalized treatment.
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Affiliation(s)
- Nicholas Ng
- Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland.
| | - Matilde Mijares Zamuner
- Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Najia Siddique
- Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Joon Kim
- Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Marie Burke
- Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Maria Michele Byrne
- Department of Diabetes and Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland
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9
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Rafique I, Mir A, Siddiqui S, Saqib MAN, Fawwad A, Marchand L, Adnan M, Naeem M, Basit A, Polychronakos C. Comprehensive genetic screening reveals wide spectrum of genetic variants in monogenic forms of diabetes among Pakistani population. World J Diabetes 2021; 12:1957-1966. [PMID: 34888019 PMCID: PMC8613659 DOI: 10.4239/wjd.v12.i11.1957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/14/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Monogenic forms of diabetes (MFD) are single gene disorders. Their diagnosis is challenging, and symptoms overlap with type 1 and type 2 diabetes.
AIM To identify the genetic variants responsible for MFD in the Pakistani population and their frequencies.
METHODS A total of 184 patients suspected of having MFD were enrolled. The inclusion criterion was diabetes with onset below 25 years of age. Brief demographic and clinical information were taken from the participants. The maturity-onset diabetes of the young (MODY) probability score was calculated, and glutamate decarboxylase ELISA was performed. Antibody negative patients and features resembling MODY were selected (n = 28) for exome sequencing to identify the pathogenic variants.
RESULTS A total of eight missense novel or very low-frequency variants were identified in 7 patients. Three variants were found in genes for MODY, i.e. HNF1A (c.169C>A, p.Leu57Met), KLF11 (c.401G>C, p.Gly134Ala), and HNF1B (c.1058C>T, p.Ser353Leu). Five variants were found in genes other than the 14 known MODY genes, i.e. RFX6 (c.919G>A, p.Glu307Lys), WFS1 (c.478G>A, p.Glu160Lys) and WFS1 (c.517G>A, p.Glu173Lys), RFX6 (c.1212T>A, p.His404Gln) and ZBTB20 (c.1049G>A, p.Arg350His).
CONCLUSION The study showed wide spectrum of genetic variants potentially causing MFD in the Pakistani population. The MODY genes prevalent in European population (GCK, HNF1A, and HNF4a) were not found to be common in our population. Identification of novel variants will further help to understand the role of different genes causing the pathogenicity in MODY patient and their proper management and diagnosis.
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Affiliation(s)
- Ibrar Rafique
- Department of Biological Sciences, International Islamic University, Islamabad 44000, Pakistan
- Departments of Pediatrics and Human Genetics, McGill University Health Centre Research Institute, Montreal H4A 3J1, Canada
- Research Development and Coordination, Pakistan Health Research Council, Islamabad 44000, Pakistan
| | - Asif Mir
- Department of Biological Sciences, International Islamic University, Islamabad 44000, Pakistan
| | - Shajee Siddiqui
- Department of Medicine, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan, Pakistan
| | | | - Asher Fawwad
- Department of Biochemistry, Baqai Institute of Diabetology and Endocrinology, Baqai Medical University, Karachi 74600, Sindh, Pakistan
| | - Luc Marchand
- Departments of Pediatrics and Human Genetics, McGill University Health Centre Research Institute, Montreal H4A 3J1, Canada
| | - Muhammad Adnan
- PHRC Research Centre, FJMU, Pakistan Health Research Council, Lahore 54000, Pakistan
| | - Muhammad Naeem
- Department of Biotechnology, Quaid-I-Azam University, Islamabad 44000, Pakistan
| | - Abdul Basit
- Department of Medicine, Baqai Institute of Diabetology and Endocrinology, Baqai Medical University, Karachi 74600, Sindh, Pakistan
| | - Constantin Polychronakos
- Departments of Pediatrics and Human Genetics, McGill University Health Centre Research Institute, Montreal H4A 3J1, Canada
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Yoshida K, Mushimoto Y, Tanase-Nakao K, Akiba K, Ishii K, Urakami T, Sugihara S, Kikuchi T, Fukami M, Narumi S. A case report with functional characterization of a HNF1B mutation (p.Leu168Pro) causing MODY5. Clin Pediatr Endocrinol 2021; 30:179-185. [PMID: 34629740 PMCID: PMC8481079 DOI: 10.1297/cpe.30.179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/20/2021] [Indexed: 11/25/2022] Open
Abstract
We previously performed next-generation sequencing-based genetic screening in patients
with autoantibody-negative type 1 diabetes, and identified the p.Leu168Pro mutation in
HNF1B. Here,we report the clinical course of the patient and
the results of functional characterization of this mutation. The proband had bilateral
renal hypodysplasia and developed insulin-dependent diabetes during childhood. The
pathogenicity of Leu168Pro-HNF1B was evaluated with three-dimensional structure modeling,
Western blotting, immunofluorescence analysis and luciferase reporter assays using human
embryonic kidney 293 cells. Three-dimensional structure modeling predicted that the Leu168
residue is buried in the DNA-binding Pit-Oct-Unc-specific (POUS) domain and
forms a hydrophobic core. Western blotting showed that the protein expression level of
Leu168Pro-HNF1B was lower than that of wild-type (WT) HNF1B. Immunofluorescence staining
showed that both WT- and Leu168Pro-HNF1B were normally localized in the nucleus. The cells
transfected with WT-HNF1B exhibited 5-fold higher luciferase reporter activity than cells
transfected with an empty vector. The luciferase activities were comparable between
WT-HNF1B/Leu168Pro-HNF1B and WT-HNF1B/empty vector co-transfection. In conclusion,
Leu168Pro is a protein-destabilizing HNF1B mutation, and the
destabilization is likely due to the structural changes involving the hydrophobic core of
POUS. The disease-causing Leu168Pro HNF1B mutation is a
loss-of-function mutation without a dominant-negative effect.
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Affiliation(s)
- Kei Yoshida
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.,Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Yuichi Mushimoto
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kanako Tanase-Nakao
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Kazuhisa Akiba
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Kanako Ishii
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tatsuhiko Urakami
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Shigetaka Sugihara
- Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan
| | - Toru Kikuchi
- Department of Pediatrics, Saitama Medical University, Saitama, Japan
| | - Maki Fukami
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Satoshi Narumi
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
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11
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Acquired Evolution of Mitochondrial Metabolism Regulated by HNF1B in Ovarian Clear Cell Carcinoma. Cancers (Basel) 2021; 13:cancers13102413. [PMID: 34067626 PMCID: PMC8157013 DOI: 10.3390/cancers13102413] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 01/11/2023] Open
Abstract
Clear cell carcinoma (CCC) of the ovary exhibits a unique morphology and clinically malignant behavior. The eosinophilic cytoplasm includes abundant glycogen. Although the growth is slow, the prognosis is poor owing to resistance to conventional chemotherapies. CCC often arises in endometriotic cysts and is accompanied by endometriosis. Based on these characteristics, three clinical questions are considered: why does ovarian cancer, especially CCC and endometrioid carcinoma, frequently occur in endometriotic cysts, why do distinct histological subtypes (CCC and endometrioid carcinoma) arise in the endometriotic cyst, and why does ovarian CCC possess unique characteristics? Mutations in AT-rich interacting domain-containing protein 1A and phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit alpha genes may contribute to the carcinogenesis of ovarian CCC, whereas hepatocyte nuclear factor-1-beta (HNF1B) plays crucial roles in sculpting the unique characteristics of ovarian CCC through metabolic alterations. HNF1B increases glutathione synthesis, activates anaerobic glycolysis called the Warburg effect, and suppresses mitochondria. These metabolic changes may be induced in stressful environments. Life has evolved to utilize and control energy; eukaryotes require mitochondria to transform oxygen reduction into useful energy. Because mitochondrial function is suppressed in ovarian CCC, these cancer cells probably acquired further metabolic evolution during the carcinogenic process in order to survive stressful environments.
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12
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Cho J, Horikawa Y, Enya M, Takeda J, Imai Y, Imai Y, Handa H, Imai T. L-Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic β-cells. Commun Biol 2020; 3:497. [PMID: 32901087 PMCID: PMC7479149 DOI: 10.1038/s42003-020-01226-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 08/13/2020] [Indexed: 12/23/2022] Open
Abstract
We sought to determine a mechanism by which L-arginine increases glucose-stimulated insulin secretion (GSIS) in β-cells by finding a protein with affinity to L-arginine using arginine-immobilized magnetic nanobeads technology. Glucokinase (GCK), the key regulator of GSIS and a disease-causing gene of maturity-onset diabetes of the young type 2 (MODY2), was found to bind L-arginine. L-Arginine stimulated production of glucose-6-phosphate (G6P) and induced insulin secretion. We analyzed glucokinase mutants and identified three glutamate residues that mediate binding to L-arginine. One MODY2 patient with GCKE442* demonstrated lower C-peptide-to-glucose ratio after arginine administration. In β-cell line, GCKE442* reduced L-arginine-induced insulin secretion compared with GCKWT. In addition, we elucidated that the binding of arginine protects glucokinase from degradation by E3 ubiquitin ligase cereblon mediated ubiquitination. We conclude that L-arginine induces insulin secretion by increasing G6P production by glucokinase through direct stimulation and by prevention of degradation. Using arginine-immobilized magnetic nanobeads, Cho et al. show that glucokinase, the key regulator of glucose-stimulated insulin secretion, binds L-arginine, which protects glucokinase from ubiquitination-mediated degradation while inducing insulin secretion. This study provides mechanistic insights into how L-arginine increases insulin production.
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Affiliation(s)
- Jaeyong Cho
- Department Aging Intervention, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan
| | - Yukio Horikawa
- Department of Diabetes and Endocrinology, Gifu University, Gifu, Gifu, 501-1194, Japan
| | - Mayumi Enya
- Department of Diabetes and Endocrinology, Gifu University, Gifu, Gifu, 501-1194, Japan
| | - Jun Takeda
- Department of Diabetes and Endocrinology, Gifu University, Gifu, Gifu, 501-1194, Japan
| | - Yoichi Imai
- Department of Hematology/Oncology, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan
| | - Yumi Imai
- Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Hiroshi Handa
- Department of Nanoparticle Translational Research, Tokyo Medical University, Shinjyuku, Tokyo, 160-8402, Japan
| | - Takeshi Imai
- Department Aging Intervention, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.
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13
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Terakawa A, Chujo D, Yasuda K, Ueno K, Nakamura T, Hamano S, Ohsugi M, Tanabe A, Ueki K, Kajio H. Maturity-Onset diabetes of the young type 5 treated with the glucagon-like peptide-1 receptor agonist: A case report. Medicine (Baltimore) 2020; 99:e21939. [PMID: 32871938 PMCID: PMC7458169 DOI: 10.1097/md.0000000000021939] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
RATIONALE Maturity-onset diabetes of the young type 5 (MODY 5) is a form of monogenic diabetes that is often accompanied by pancreatic dysfunction. To date, no cases of MODY 5 treated with glucagon-like peptide-1 receptor agonist (GLP-1RA) have been reported. We present the first case of MODY 5 treated with GLP-1RA. PATIENT CONCERNS A 17-year-old woman, with a history of being operated for congenital ileal atresia at birth, was admitted to our hospital due to hyperglycemia. She had been clinically diagnosed with type 1 diabetes 1 month prior, and administered 14 units of insulin glargine 300 U/mL per day. DIAGNOSIS She had hypopotassemia, hypomagnesaemia, pancreatic body, and tail defects, multiple renal cysts, and a family history of diabetes, and urogenital anomaly. Genetic testing revealed heterozygous deletion of hepatocyte nuclear transcription factor-1 beta, leading to the diagnosis of MODY 5. INTERVENTIONS The patient was treated with multiple daily insulin injections for 9 days (22 units/d) before administration of GLP-1RA, and then liraglutide was initiated. OUTCOMES Liraglutide treatment (0.6 mg/d) alone maintained the patient's glycated hemoglobin level below 7.0% for at least 12 months after discharge. A higher dose, 0.9 mg/d, of liraglutide was not tolerated by the patient due to nausea. Serum levels of C-peptide immunoreactivity were 1.15 ng/mL and 1.91 ng/mL, respectively, after 6 and 12 months of liraglutide therapy. LESSONS GLP-1RA might be effective at regulating glucose metabolism by utilizing residual pancreatic endocrine function in patients with MODY 5. Imaging and genetic screening were helpful in the diagnosis of MODY 5.
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Affiliation(s)
- Aiko Terakawa
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Daisuke Chujo
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
- Center for Clinical Research, Toyama University Hospital, Toyama
| | - Kazuki Yasuda
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University, Mitaka
| | - Keisuke Ueno
- Department of Diabetes and Endocrinology, Tokyo Shinjuku Medical Center
| | - Tomoka Nakamura
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Shoko Hamano
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
- Mishuku Hospital, Tokyo, Japan
| | - Mitsuru Ohsugi
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Akiyo Tanabe
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Kohjiro Ueki
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Hiroshi Kajio
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
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14
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Omura Y, Yagi K, Honoki H, Iwata M, Enkaku A, Takikawa A, Kuwano T, Watanabe Y, Nishimura A, Liu J, Chujo D, Fujisaka S, Enya M, Horikawa Y, Tobe K. Clinical manifestations of a sporadic maturity-onset diabetes of the young (MODY) 5 with a whole deletion of HNF1B based on 17q12 microdeletion. Endocr J 2019; 66:1113-1116. [PMID: 31391355 DOI: 10.1507/endocrj.ej19-0020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
We report a sporadic case of maturity-onset diabetes of the young type 5 (MODY5) with a whole-gene deletion of the hepatocyte nuclear factor-1beta (HNF1B) gene. A 44-year-old Japanese man who had been diagnosed with early-onset non-autoimmune diabetes mellitus at the age of 23 was examined. He showed multi-systemic symptoms, including a solitary congenital kidney, pancreatic hypoplasia, pancreatic exocrine dysfunction, elevation of the serum levels of liver enzymes, hypomagnesemia, and hyperuricemia. These clinical characteristics, in spite of the absence of a family history of diabetes, prompted us to make the diagnosis of maturity-onset diabetes of the young 5 (MODY 5). One allele deletion of the entire HNF1B gene revealed by multiplex ligation-dependent probe amplification (MLPA) led us to the diagnoses of 17q12 microdeletion syndrome even though there were negative chromosomal analyses with array comparative genomic hybridization (CGH). 17q12 microdeletion syndrome, which is not rare especially in sporadic cases since 17q12 is a typical hot spot for chromosomal deletion, could have complicated the clinical heterogeneity of MODY5.
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Affiliation(s)
- Yoshiyuki Omura
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Kunimasa Yagi
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Hisae Honoki
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Minoru Iwata
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Asako Enkaku
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Akiko Takikawa
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Takahide Kuwano
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Yoshiyuki Watanabe
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Ayumi Nishimura
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Jianhui Liu
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Daisuke Chujo
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Shiho Fujisaka
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Mayumi Enya
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yukio Horikawa
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Kazuyuki Tobe
- 1st Department of Internal Medicine, University of Toyama, Toyama, Japan
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15
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Dotto RP, de Santana LS, Lindsey SC, Caetano LA, Franco LF, Moisés RCMS, Sa JR, Nishiura JL, Teles MG, Heilberg IP, Dias-da-Silva MR, Giuffrida FMA, Reis AF. Searching for mutations in the HNF1B gene in a Brazilian cohort with renal cysts and hyperglycemia. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2019; 63:250-257. [PMID: 31066763 PMCID: PMC10522195 DOI: 10.20945/2359-3997000000138] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 02/13/2019] [Indexed: 01/27/2023]
Abstract
OBJECTIVE To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. SUBJECTS AND METHODS We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. RESULTS We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. CONCLUSION The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).
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Affiliation(s)
- Renata P. Dotto
- Universidade Federal de São PauloDisciplina de EndocrinologiaDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Endocrinologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - Lucas Santos de Santana
- Universidade de São PauloUnidade de Endocrinologia Genética/LIM25Faculdade de MedicinaUniversidade de São PauloSão PauloSPBrasilGrupo de Diabetes Monogênico, Unidade de Endocrinologia Genética/LIM25, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Susan C. Lindsey
- Universidade Federal de São PauloDisciplina de EndocrinologiaDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Endocrinologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - Lilian Araújo Caetano
- Universidade de São PauloUnidade de Endocrinologia Genética/LIM25Faculdade de MedicinaUniversidade de São PauloSão PauloSPBrasilGrupo de Diabetes Monogênico, Unidade de Endocrinologia Genética/LIM25, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Luciana F. Franco
- Universidade Federal de São PauloDisciplina de EndocrinologiaDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Endocrinologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - Regina Célia M. S. Moisés
- Universidade Federal de São PauloDisciplina de EndocrinologiaDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Endocrinologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - João R. Sa
- Universidade Federal de São PauloDisciplina de EndocrinologiaDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Endocrinologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - José Luiz Nishiura
- Universidade Federal de São PauloDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - Milena Gurgel Teles
- Universidade de São PauloUnidade de Endocrinologia Genética/LIM25Faculdade de MedicinaUniversidade de São PauloSão PauloSPBrasilGrupo de Diabetes Monogênico, Unidade de Endocrinologia Genética/LIM25, Faculdade de Medicina, Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
| | - Ita P. Heilberg
- Universidade Federal de São PauloDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - Magnus R. Dias-da-Silva
- Universidade Federal de São PauloDisciplina de EndocrinologiaDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Endocrinologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - Fernando M. A. Giuffrida
- Universidade Federal de São PauloDisciplina de EndocrinologiaDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Endocrinologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
- Universidade do Estado da BahiaDepartamento de Ciências da VidaUniversidade do Estado da BahiaSalvadorBABrasilDepartamento de Ciências da Vida, Universidade do Estado da Bahia (UNEB), Salvador, BA, Brasil
| | - André F. Reis
- Universidade Federal de São PauloDisciplina de EndocrinologiaDepartamento de MedicinaUniversidade Federal de São PauloSão PauloSPBrasilDisciplina de Endocrinologia, Departamento de Medicina, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
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Abstract
PURPOSE OF REVIEW MODY6 due to mutations in the gene NEUROD1 is very rare, and details on its clinical manifestation and pathogenesis are scarce. In this review, we have summarized all reported cases of MODY6 diagnosed by genetic testing, and examined their clinical features in detail. RECENT FINDINGS MODY6 is a low penetrant MODY, suggesting that development of the disease is affected by genetic modifying factors, environmental factors, and/or the effects of interactions of genetic and environmental factors, as is the case with MODY5. Furthermore, while patients with MODY6 can usually achieve good glycemic control without insulin, when undiagnosed they are prone to become ketotic with chronic hyperglycemia, and microangiopathy can progress. MODY6 may also cause neurological abnormalities such as intellectual disability. MODY6 should be diagnosed early and definitively by genetic testing, so that the correct treatment can be started as soon as possible to prevent chronic hyperglycemia.
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Affiliation(s)
- Yukio Horikawa
- Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu city, Gifu, 501-1194, Japan.
| | - Mayumi Enya
- Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu city, Gifu, 501-1194, Japan
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17
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Kato T, Tanaka D, Muro S, Jambaljav B, Mori E, Yonemitsu S, Oki S, Inagaki N. A Novel p.L145Q Mutation in the HNF1B Gene in a Case of Maturity-onset Diabetes of the Young Type 5 (MODY5). Intern Med 2018; 57:2035-2039. [PMID: 29491316 PMCID: PMC6096008 DOI: 10.2169/internalmedicine.9692-17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of early onset diabetes. The hepatocyte nuclear factor-1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5) with distinctive clinical features, including pancreatic atrophy and renal disease. We herein report a Japanese case of young-onset diabetes with typical phenotypes of MODY5 and a novel heterozygous missense mutation (p.L145Q) in the HNF1B gene. The mutation was located in the Pit-Oct-Unc (POU)-specific domain, and the amino acid residue L145 was highly conserved among species. It is strongly suggested that this mutation explains the phenotypes of MODY5.
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Affiliation(s)
- Tomoko Kato
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Japan
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Daisuke Tanaka
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Japan
| | - Seiji Muro
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Byambatseren Jambaljav
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Japan
| | - Eisaku Mori
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Shin Yonemitsu
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Shogo Oki
- Department of Diabetes and Endocrinology, Osaka Red Cross Hospital, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Japan
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18
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No novel, high penetrant gene might remain to be found in Japanese patients with unknown MODY. J Hum Genet 2018; 63:821-829. [PMID: 29670293 DOI: 10.1038/s10038-018-0449-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 03/07/2018] [Accepted: 03/09/2018] [Indexed: 11/08/2022]
Abstract
MODY 5 and 6 have been shown to be low-penetrant MODYs. As the genetic background of unknown MODY is assumed to be similar, a new analytical strategy is applied here to elucidate genetic predispositions to unknown MODY. We examined to find whether there are major MODY gene loci remaining to be identified using SNP linkage analysis in Japanese. Whole-exome sequencing was performed with seven families with typical MODY. Candidates for novel MODY genes were examined combined with in silico network analysis. Some peaks were found only in either parametric or non-parametric analysis; however, none of these peaks showed a LOD score greater than 3.7, which is approved to be the significance threshold of evidence for linkage. Exome sequencing revealed that three mutated genes were common among 3 families and 42 mutated genes were common in two families. Only one of these genes, MYO5A, having rare amino acid mutations p.R849Q and p.V1601G, was involved in the biological network of known MODY genes through the intermediary of the INS. Although only one promising candidate gene, MYO5A, was identified, no novel, high penetrant MODY genes might remain to be found in Japanese MODY.
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19
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Horikawa Y. Maturity-onset diabetes of the young as a model for elucidating the multifactorial origin of type 2 diabetes mellitus. J Diabetes Investig 2018; 9:704-712. [PMID: 29406598 PMCID: PMC6031504 DOI: 10.1111/jdi.12812] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 01/30/2018] [Accepted: 01/30/2018] [Indexed: 12/19/2022] Open
Abstract
Maturity‐onset diabetes of the young (MODY) is a form of diabetes classically characterized as having autosomal dominant inheritance, onset before the age of 25 years in at least one family member and partly preserved pancreatic β‐cell function. The 14 responsible genes are reported to be MODY type 1~14, of which MODY 2 and 3 might be the most common forms. Although MODY is currently classified as diabetes of a single gene defect, it has become clear that mutations in rare MODYs, such as MODY 5 and MODY 6, have small mutagenic effects and low penetrance. In addition, as there are differences in the clinical phenotypes caused by the same mutation even in the same family, other phenotypic modifying factors are thought to exist; MODY could well have characteristics of type 2 diabetes mellitus, which is of multifactorial origin. Here, we outline the effects of genetic and environmental factors on the known phenotypes of MODY, focusing mainly on the examples of MODY 5 and 6, which have low penetrance, as suggestive models for elucidating the multifactorial origin of type 2 diabetes mellitus.
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Affiliation(s)
- Yukio Horikawa
- Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu, Japan
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Horikawa Y, Enya M, Mabe H, Fukushima K, Takubo N, Ohashi M, Ikeda F, Hashimoto KI, Watada H, Takeda J. NEUROD1-deficient diabetes (MODY6): Identification of the first cases in Japanese and the clinical features. Pediatr Diabetes 2018; 19:236-242. [PMID: 28664602 DOI: 10.1111/pedi.12553] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 05/26/2017] [Accepted: 05/31/2017] [Indexed: 12/13/2022] Open
Abstract
AIMS Only a few families with neuronal differentiation 1 (NEUROD1)-deficient diabetes, currently designated as maturity-onset diabetes of the young 6 (MODY6), have been reported, but mostly in Caucasian, and no mutation has been identified by family-based screening in Japanese. Accordingly, the phenotypic details of the disease remain to be elucidated. METHODS We examined a total of 275 subjects having diabetes suspected to be MODY who were negative for mutations in MODY1-5 referred from 155 medical institutions throughout Japan. So as not to miss low penetrant cases, we examined non-obese Japanese patients with early-onset diabetes regardless of the presence of family history by direct sequencing of all exons and flanking regions of NEUROD1 . Large genomic rearrangements also were examined. RESULTS Four patients with 3 frameshift mutations and 1 missense mutation, all of which were heterozygous and 3 of which were novel, were identified. Diabetic ketosis was found occasionally in these patients even under conditions of chronic hyperglycemia, for unknown reasons. Although the capacity of early-phase insulin secretion was low in these patients, the insulin secretory capacity was relatively preserved compared to that in hepatocyte nuclear factor (HNF)1A- and HNF1B-MODY. One of the patients and 2 of their diabetic mothers were found to have some mental or neuronal abnormality. CONCLUSIONS This is the first report of NEUROD1 mutations in Japanese, who have a genetic background of intrinsically lower capacity of insulin secretion. NEUROD1-deficient diabetes appears to be low penetrant, and may occur in concert with other genetic factors.
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Affiliation(s)
- Yukio Horikawa
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.,Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan
| | - Mayumi Enya
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.,Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan
| | - Hiroyo Mabe
- Department of Child Development, Kumamoto University Hospital, Kumamoto, Japan
| | - Kei Fukushima
- Department of Pediatrics, Juntendo University Hospital, Tokyo, Japan
| | - Noriyuki Takubo
- Department of Pediatrics, Juntendo University Hospital, Tokyo, Japan
| | - Masaaki Ohashi
- Department of Diabetes and Endocrinology, Saku Central Hospital, Nagano, Japan
| | - Fuki Ikeda
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ken-Ichi Hashimoto
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.,Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan
| | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Jun Takeda
- Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.,Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan
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Dubois-Laforgue D, Cornu E, Saint-Martin C, Coste J, Bellanné-Chantelot C, Timsit J. Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B ( HNF1B) Molecular Defects. Diabetes Care 2017; 40:1436-1443. [PMID: 28420700 DOI: 10.2337/dc16-2462] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 03/21/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Molecular defects of hepatocyte nuclear factor 1B (HNF1B) are associated with a multiorgan disease, including diabetes (maturity-onset diabetes of the young 5) and kidney abnormalities. The HNF1B syndrome is related to HNF1B mutations or to a 17q12 deletion spanning 15 genes, including HNF1B. Here, we described HNF1B-related diabetes and associated phenotypes and assessed genotype/phenotype correlations at diagnosis and in the long-term. RESEARCH DESIGN AND METHODS This multicenter retrospective cohort study included 201 patients, aged 18 years or older at follow-up, with HNF1B mutations (n = 101) or deletion (n = 100). RESULTS Diabetes was present in 159 patients. At diagnosis, clinical symptoms of diabetes were present in 67 of 144 patients and HNF1B renal disease in 64 of 102. Although responsiveness to sulfonylureas/repaglinide was observed in 29 of the 51 tested, 111 of 140 patients (79%) were treated with insulin at follow-up. Diabetic retinopathy and/or neuropathy were present in 46 of 114 patients. Renal cysts were present in 122 of 166 patients, chronic kidney disease stages 3-4 (CKD3-4) in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%). Compared with the patients with mutations, those with HNF1B deletion less often had CKD3-4/ESRD at diagnosis (11 of 43 vs. 27 of 35, P < 10-4) and in the long term (40 of 78 vs. 71 of 91, P = 0.0003). They were leaner and more frequently treated with insulin. CONCLUSIONS In patients with HNF1B syndrome, diabetes complications, cardiovascular risk factors, CKD3-4, and ESRD are highly prevalent. At diabetes diagnosis, the presence of morphological and/or functional kidney disease may help etiological diagnosis. Genotype/phenotype correlations may have implications for the care and the prognosis of these patients.
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Affiliation(s)
- Danièle Dubois-Laforgue
- Department of Diabetology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, and Paris Descartes University, DHU AUTHORS, Paris, France .,INSERM U1016, Cochin Hospital, Paris, France
| | - Erika Cornu
- Department of Diabetology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, and Paris Descartes University, DHU AUTHORS, Paris, France
| | - Cécile Saint-Martin
- Department of Genetics, Pitié-Salpétrière Hospital, Assistance Publique-Hôpitaux de Paris, and Pierre et Marie Curie University, Paris, France
| | - Joël Coste
- Department of Biostatistics and Epidemiology, Hôtel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, and Paris Descartes University, Paris, France
| | - Christine Bellanné-Chantelot
- Department of Genetics, Pitié-Salpétrière Hospital, Assistance Publique-Hôpitaux de Paris, and Pierre et Marie Curie University, Paris, France
| | - José Timsit
- Department of Diabetology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, and Paris Descartes University, DHU AUTHORS, Paris, France
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Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese. Mol Genet Metab Rep 2014; 1:350-361. [PMID: 27896108 PMCID: PMC5121356 DOI: 10.1016/j.ymgmr.2014.07.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 07/26/2014] [Accepted: 07/26/2014] [Indexed: 02/08/2023] Open
Abstract
Background None of the high frequency variants of the incretin-related genes has been found by genome-wide association study (GWAS) for association with occurrence of type 2 diabetes in Japanese. However, low frequency and rare and/or high frequency variants affecting glucose metabolic traits remain to be investigated. Method We screened all exons of the incretin-related genes (GCG, GLP1R, DPP4, PCSK1, GIP, and GIPR) in 96 patients with type 2 diabetes and investigated for association of genetic variants of these genes with quantitative metabolic traits upon test meal with 38 young healthy volunteers and with the occurrence of type 2 diabetes in Japanese subjects comprising 1303 patients with type 2 diabetes and 1014 controls. Result Two mutations of GIPR, p.Thr3Alafsx21 and Arg183Gln, were found only in patients with type 2 diabetes, and both of them were treated with insulin. Of ten tagSNPs, we found that risk allele C of SNP393 (rs6235) of PCSK1 was nominally associated with higher fasting insulin and HOMA-R (P = 0.034 and P = 0.030), but not with proinsulin level, incretin level or BMI. The variant showed significant association with occurrence of type 2 diabetes after adjustment for age, sex, and BMI (P = 0.0043). Conclusion Rare variants of GIPR may contribute to the development of type 2 diabetes, possibly through insulin secretory defects. Furthermore, the genetic variant of PCSK1 might influence glucose homeostasis by altered insulin resistance independently of BMI, incretin level or proinsulin conversion, and may be associated with the occurrence of type 2 diabetes in Japanese.
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Key Words
- BMI, body mass index
- CPR, c-peptide immunoreactivity
- DPP4, dipeptidyl peptidase 4
- GCG, proglucagon gene
- GIP, glucose-dependent insulinotropic peptide
- GIPR, GIP receptor
- GLP-1, glucagon-like peptide 1
- GLP1R, GLP-1 receptor
- GWAS, genome-wide association study
- HOMA-B, homeostasis model assessment as an index of insulin secretion
- HOMA-R, homeostasis model assessment as an index of insulin resistance
- HbA1c, hemoglobin A1c
- IRI, immunoreactive insulin
- Incretin
- LD, linkage disequilibrium
- OR, odds ratio
- Obesity
- PCR, polymerase chain reaction
- PCSK1
- PCSK1, prohormone convertase (PC) enzymes. PC1/3
- Polymorphism
- SNP, single nucleotide polymorphism
- Type 2 diabetes
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