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Iqbal J, Jiang HL, Wu HX, Li L, Zhou YH, Hu N, Xiao F, Wang T, Xu SN, Zhou HD. Hereditary severe insulin resistance syndrome: Pathogenesis, pathophysiology, and clinical management. Genes Dis 2022. [PMID: 37492723 PMCID: PMC10363564 DOI: 10.1016/j.gendis.2022.03.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Severe insulin resistance has been linked to some of the most globally prevalent disorders, such as diabetes mellitus, nonalcoholic fatty liver disease, polycystic ovarian syndrome, and hypertension. Hereditary severe insulin resistance syndrome (H-SIRS) is a rare disorder classified into four principal categories: primary insulin receptor defects, lipodystrophies, complex syndromes, and obesity-related H-SIRS. Genes such as INSR, AKT2, TBC1D4, AGPAT2, BSCL2, CAV1, PTRF, LMNA, PPARG, PLIN1, CIDEC, LIPE, PCYT1A, MC4R, LEP, POMC, SH2B1, RECQL2, RECQL3, ALMS1, PCNT, ZMPSTE24, PIK3R1, and POLD1 have been linked to H-SIRS. Its clinical features include insulin resistance, hyperglycemia, hyperandrogenism, severe dyslipidemia, fatty liver, abnormal topography of adipose tissue, and low serum leptin and adiponectin levels. Diagnosis of H-SIRS is based on the presence of typical clinical features associated with the various H-SIRS forms and the identification of mutations in H-SIRS-linked genes by genetic testing. Diet therapy, insulin sensitization, exogenous insulin therapy, and leptin replacement therapy have widely been adopted to manage H-SIRS. The rarity of H-SIRS, its highly variable clinical presentation, refusal to be tested for genetic mutations by patients' family members who are not severely sick, unavailability of genetic testing, and testing expenses contribute to the delayed or underdiagnoses of H-SIRS. Early diagnosis facilitates early management of the condition, which results in improved glycemic control and delayed onset of diabetes and other complications related to severe insulin resistance. The use of updated genetic sequencing technologies is recommended, and long-term studies are required for genotype-phenotype differentiation and formulation of diagnostic and treatment protocols.
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Yan FF, Huang BK, Chen YL, Zhuang YZ, You XY, Liu CQ, Li XJ. Coexistence of ovarian serous papillary cystadenofibroma and type A insulin resistance syndrome in a 14-year-old girl: A case report. World J Clin Cases 2020; 8:3334-3340. [PMID: 32874990 PMCID: PMC7441255 DOI: 10.12998/wjcc.v8.i15.3334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/27/2020] [Accepted: 07/14/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Type A insulin resistance syndrome is a rare disorder caused by mutations in the gene encoding the insulin receptor. Its coexistence with ovarian serous papillary cystadenofibroma is even rarer.
CASE SUMMARY A 14-year-old girl developed type A insulin resistance syndrome and showed high fasting insulin, glucose, and hemoglobin A1c (HbA1c) levels. The girl suffered from ovarian serous papillary cystadenofibroma. The laboratory results were as follows: fasting insulin was 2624.90 pmol/L and HbA1c was 8.5%. A heterozygous missense mutation on exon 20 of the insulin receptor gene (c.3601C>T, Arg1201Trp) was observed. The histopathological diagnosis was a cystic lesion that extended to the upper right uterus, indicating a right ovarian serous papillary cystadefibroma accompanied by focal interstitial hyperplasia. The patient was treated with metformin for over 6 mo. Additionally, laparoscopic resection (bilateral) of the ovarian lesion and laparoscopic intestinal adhesiolysis were performed under general anesthesia. Diet therapy combined with exercise was then initiated. The patient had an uneventful recovery. The patient also showed improved blood glucose control, with reduced levels of fasting insulin (857.84 pmol/L) and HbA1c (7.0%).
CONCLUSION Insulin resistance may play a significant role in the induction of tumors. It is important to investigate further the association between insulin resistance and tumors and the underlying mechanism.
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Affiliation(s)
- Fang-Fang Yan
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Bing-Kun Huang
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Yin-Ling Chen
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Yan-Zhen Zhuang
- Department of Pathology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Xue-Ye You
- Department of Pathology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Chang-Qin Liu
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
| | - Xue-Jun Li
- Department of Endocrinology and Diabetes, The First Affiliated Hospital of Xiamen University, Xiamen 361003, Fujian Province, China
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Rogal J, Zbinden A, Schenke-Layland K, Loskill P. Stem-cell based organ-on-a-chip models for diabetes research. Adv Drug Deliv Rev 2019; 140:101-128. [PMID: 30359630 DOI: 10.1016/j.addr.2018.10.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 09/10/2018] [Accepted: 10/19/2018] [Indexed: 12/22/2022]
Abstract
Diabetes mellitus (DM) ranks among the severest global health concerns of the 21st century. It encompasses a group of chronic disorders characterized by a dysregulated glucose metabolism, which arises as a consequence of progressive autoimmune destruction of pancreatic beta-cells (type 1 DM), or as a result of beta-cell dysfunction combined with systemic insulin resistance (type 2 DM). Human cohort studies have provided evidence of genetic and environmental contributions to DM; yet, these studies are mostly restricted to investigating statistical correlations between DM and certain risk factors. Mechanistic studies, on the other hand, aimed at re-creating the clinical picture of human DM in animal models. A translation to human biology is, however, often inadequate owing to significant differences between animal and human physiology, including the species-specific glucose regulation. Thus, there is an urgent need for the development of advanced human in vitro models with the potential to identify novel treatment options for DM. This review provides an overview of the technological advances in research on DM-relevant stem cells and their integration into microphysiological environments as provided by the organ-on-a-chip technology.
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Affiliation(s)
- Julia Rogal
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany; Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Nobelstrasse 12, 70569 Stuttgart, Germany
| | - Aline Zbinden
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany
| | - Katja Schenke-Layland
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany; The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany; Department of Medicine/Cardiology, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, 675 Charles E. Young Drive South, MRL 3645, Los Angeles, CA, USA.
| | - Peter Loskill
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany; Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Nobelstrasse 12, 70569 Stuttgart, Germany
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Azzabi O, Jilani H, Rejeb I, Siala N, Elaribi Y, Hizem S, Selmi I, Halioui S, Lascols O, Jemaa LB, Maherzi A. Arg924X homozygous mutation in insulin receptor gene in a Tunisian patient with Donohue syndrome. J Pediatr Endocrinol Metab 2016; 29:753-6. [PMID: 26974131 DOI: 10.1515/jpem-2015-0232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 01/15/2016] [Indexed: 11/15/2022]
Abstract
Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We describe a new case of Donohue syndrome born at 37 weeks' gestation of unrelated parents and presented with intra-uterine growth retardation, nipple hypertrophy, macropenis, distended abdomen, hirsutism and dysmorphic features. The clinical course showed failure to thrive, and episodes of alternating hypoglycemia and hyperglycemia. Laboratory tests revealed direct hyperbilirubinemia. The diagnosis of Donohue syndrome was established based on the above clinical characteristics and determination of the INSR mutation. He was found to have homozygous nonsense mutation c. 2270 C>T (Arg924X) at exon 14 of the INSR gene. He later developed enterocolitis and died at 3 months old. Prenatal diagnosis was performed for the family via chorionic villous biopsy. We try to explain gastrointestinal dysfunction seen in our patient.
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Choi JH, Kang M, Kim JH, Cho J, Kim GH, Yoo HW. Identification and Functional Characterization of Two Novel Nonsense Mutations in the β-Subunit of INSR That Cause Severe Insulin Resistance Syndrome. Horm Res Paediatr 2016; 84:73-8. [PMID: 26160152 DOI: 10.1159/000381624] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 03/12/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS Donohue syndrome is an extremely rare autosomal recessive disorder caused by mutations in INSR. This study describes the clinical course of a patient with Donohue syndrome, and we also evaluated the molecular and functional characteristics of 2 novel INSR mutations. METHODS Our patient was a male newborn with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, and high serum insulin levels, all of which are characteristic of Donohue syndrome. INSR mutation analysis was performed, and Western blot analysis was used to verify the effects of the novel mutations on INSR protein expression. RESULTS Direct INSR sequencing identified the following 2 novel compound heterozygous mutations in the β-subunit of INSR: p.Arg1066* and p.Gln1232*. Western blot analysis of skin fibroblasts revealed a comparable expression of the α-subunit of INSR in mutant and control samples, but reduced levels of mature INSR β-subunit protein were found in mutant INSR-expressing cells in comparison to the controls. CONCLUSIONS This study describes the clinical course of a male patient with Donohue syndrome and the molecular characteristics of 2 novel compound heterozygous mutations in INSR. These novel nonsense mutations are associated with reduced expression of the mature INSR β-subunit, which was most likely due to impaired proreceptor processing.
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Affiliation(s)
- Jin-Ho Choi
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
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Simpkin A, Cochran E, Cameron F, Dattani M, de Bock M, Dunger DB, Forsander G, Guran T, Harris J, Isaac I, Hussain K, Kleta R, Peters C, Tasic V, Williams R, Yap Kok Peng F, O'Rahilly S, Gorden P, Semple RK, Bockenhauer D. Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations. NEPHRON. PHYSIOLOGY 2014; 128:55-61. [PMID: 25358339 PMCID: PMC4369119 DOI: 10.1159/000366225] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Accepted: 07/30/2014] [Indexed: 02/02/2023]
Abstract
BACKGROUND/AIMS Donohue and Rabson-Mendenhall syndrome are rare autosomal recessive disorders caused by mutations in the insulin receptor gene, INSR. Phenotypic features include extreme insulin resistance, linear growth retardation, paucity of fat and muscle, and soft tissue overgrowth. The insulin receptor is also expressed in the kidney, where animal data suggest it plays a role in glomerular function and blood pressure (BP) regulation, yet such a role in the human kidney is untested. Patients with biallelic INSR mutations provide a rare opportunity to ascertain its role in man. METHODS Retrospective review of patients with INSR mutations. Data for BP, renal imaging, plasma creatinine and electrolyte levels, as well as urine protein, albumin and calcium excretion were sought from the treating clinicians. RESULTS From 33 patients with INSR mutations, data were available for 17 patients. Plasma creatinine was low (mean ± SD: 25 ± 9 μmol/l) and mean plasma electrolyte concentrations were within the normal range (n = 13). Systolic BP ranged between the 18th and 91st percentile for age, sex, height and weight (n = 9; mean ± SD: 49 ± 24). Twenty-four-hour urinary calcium data were available from 10 patients and revealed hypercalciuria in all (mean ± SD: 0.32 ± 0.17 mmol/kg/day; normal <0.1). Nephrocalcinosis was present in all patients (n = 17). Urinary albumin excretion (n = 7) ranged from 4.3-122.5 μg/min (mean ± SD: 32.4 ± 41.0 μg/min; normal <20). CONCLUSIONS INSR dysfunction is associated with hypercalciuria and nephrocalcinosis. No other consistent abnormality of renal function was noted. Normotension and stable glomerular function with only moderate proteinuria is in contrast to genetically modified mice who have elevated BP and progressive diabetic nephropathy.
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Affiliation(s)
- Arabella Simpkin
- UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Elaine Cochran
- Diabetes, Endocrine and Obesity Branch, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md., USA
| | - Fergus Cameron
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Vic., Australia
| | - Mehul Dattani
- UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Martin de Bock
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | - David B. Dunger
- Department of Paediatrics, University of Cambridge, Addenbrookes Hospital, Cambridge, UK
| | - Gun Forsander
- Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Tulay Guran
- Pediatric Endocrinology, Marmara University Hospital, Istanbul, Turkey
| | - Julie Harris
- The National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, UK
- Metabolic Research Laboratories, University of Cambridge, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
| | - Iona Isaac
- The National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, UK
- Metabolic Research Laboratories, University of Cambridge, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
| | - Khalid Hussain
- UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Robert Kleta
- UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Catherine Peters
- UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Velibor Tasic
- Department of Pediatric Nephrology, University Children's Hospital, Medical School, Skopje, Macedonia
| | - Rachel Williams
- Department of Paediatrics, University of Cambridge, Addenbrookes Hospital, Cambridge, UK
| | | | - Stephan O'Rahilly
- The National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, UK
- Metabolic Research Laboratories, University of Cambridge, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
| | - Philipp Gorden
- Diabetes, Endocrine and Obesity Branch, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Md., USA
| | - Robert K. Semple
- The National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, UK
- Metabolic Research Laboratories, University of Cambridge, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
| | - Detlef Bockenhauer
- UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
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Subramanian K, Fee CJ, Fredericks R, Stubbs RS, Hayes MT. Insulin receptor-insulin interaction kinetics using multiplex surface plasmon resonance. J Mol Recognit 2014; 26:643-52. [PMID: 24277609 DOI: 10.1002/jmr.2307] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2013] [Revised: 07/31/2013] [Accepted: 08/02/2013] [Indexed: 01/22/2023]
Abstract
Type 2 diabetes affects millions of people worldwide, and measuring the kinetics of insulin receptor-insulin interactions is critical to improving our understanding of this disease. In this paper, we describe, for the first time, a rapid, real-time, multiplex surface plasmon resonance (SPR) assay for studying the interaction between insulin and the insulin receptor ectodomain, isoform A (eIR-A). We used a scaffold approach in which anti-insulin receptor monoclonal antibody 83-7 (Abcam, Cambridge, UK) was first immobilized on the SPR sensorchip by amine coupling, followed by eIR-A capture. The multiplex SPR system (ProteOn XPR36™, Bio-Rad Laboratories, Hercules, CA) enabled measurement of replicate interactions with a single, parallel set of analyte injections, whereas repeated regeneration of the scaffold between measurements caused variable loss of antibody activity. Interactions between recombinant human insulin followed a two-site binding pattern, consistent with the literature, with a high-affinity site (dissociation constant K(D1) = 38.1 ± 0.9 nM) and a low-affinity site (K(D2) = 166.3 ± 7.3 nM). The predominantly monomeric insulin analogue Lispro had corresponding dissociation constants K(D1) = 73.2 ± 1.8 nM and K(D2) = 148.9 ± 6.1 nM, but the fit to kinetic data was improved when we included a conformational change factor in which the high-affinity site was converted to the low-affinity site. The new SPR assay enables insulin-eIR-A interactions to be followed in real time and could potentially be extended to study the effects of humoral factors on the interaction, without the need for insulin labeling.
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Affiliation(s)
- Kannan Subramanian
- Biomolecular Interaction Centre and Department of Chemical and Process Engineering, University of Canterbury, Private Bag 4800, Christchurch, New Zealand, 8041
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Koklu E, Ariguloglu EA, Koklu S. Leprechaunism (Donohue syndrome): report of a case in a newborn. J Pediatr Endocrinol Metab 2014; 27:207-8. [PMID: 24127532 DOI: 10.1515/jpem-2013-0341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 08/26/2013] [Indexed: 11/15/2022]
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Ardon O, Procter M, Tvrdik T, Longo N, Mao R. Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene. Mol Genet Metab Rep 2014; 1:71-84. [PMID: 27896077 PMCID: PMC5121292 DOI: 10.1016/j.ymgmr.2013.12.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 12/24/2013] [Indexed: 02/07/2023] Open
Abstract
Mutations in the insulin receptor gene cause the inherited insulin resistant syndromes Leprechaunism and Rabson–Mendenhall syndrome. These recessive conditions are characterized by intrauterine and post-natal growth restrictions, dysmorphic features, altered glucose homeostasis, and early demise. The insulin receptor gene (INSR) maps to the short arm of chromosome 19 and is composed of 22 exons. Here we optimize the conditions for sequencing this gene and report novel mutations in patients with severe insulin resistance. Methods PCR amplification of the 22 coding exons of the INSR gene was performed using M13-tailed primers. Bidirectional DNA sequencing was performed with BigDye Terminator chemistry and M13 primers and the product was analyzed on the ABI 3100 genetic analyzer. Data analysis was performed using Mutation Surveyor software comparing the sequence to a reference INSR sequence (Genbank NC_000019). Results We sequenced four patients with Leprechaunism or Rabson–Mendenhall syndromes as well as seven samples from normal individuals and confirmed previously identified mutations in the affected patients. Three of the four mutations identified in this group caused premature insertion of a stop codon. In addition, the INSR gene was sequenced in 14 clinical samples from patients with suspected insulin resistance and one novel mutation was found in an infant with a suspected diagnosis of Leprechaunism. Discussion Leprechaunism and Rabson–Mendenhall syndrome are very rare and difficult to diagnose. Diagnosis is currently based mostly on clinical criteria. Clinical availability of DNA sequencing can provide an objective way of confirming or excluding the diagnosis.
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Affiliation(s)
- O Ardon
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - M Procter
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
| | - T Tvrdik
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA
| | - N Longo
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - R Mao
- ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
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Planchenault D, Martin-Coignard D, Rugemintwaza D, Bah AG, Cosson L, Labarthe F, Chantepie A, Saliba E. Le syndrome de Donohue ou lepréchaunisme : à propos d’un cas. Arch Pediatr 2014; 21:206-10. [DOI: 10.1016/j.arcped.2013.11.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 10/21/2013] [Accepted: 11/22/2013] [Indexed: 01/07/2023]
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Baqir ZS, Al-Lawati TT, Al Hussaini SO, Al-Sinani A, Al-Said K, Al-Rashdi I. A novel leprechaunism mutation, Cys807Arg, in an Arab infant: a rare cause of hypoglycaemia. Paediatr Int Child Health 2012; 32:183-5. [PMID: 22824672 DOI: 10.1179/2046905512y.0000000004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Leprechaunism is a rare autosomal recessive disorder which is usually fatal in early infancy or childhood. There is a paucity of genetic data on leprechaunism in the Arab population. A 4-month-old boy presented with jaundice, asymptomatic hypoglycaemia and growth retardation with features of leprechaunism. A novel Cys807Arg was identified, which could facilitate antenatal diagnosis for families in the Middle East.
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Affiliation(s)
- Zaineb S Baqir
- Division of Child Health, Royal Hospital, Bowsher, Muscat, Sultanate of Oman
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Huang Z, Li Y, Tang T, Xu W, Liao Z, Yao B, Hu G, Weng J. Hyperinsulinaemic hypoglycaemia associated with a heterozygous missense mutation of R1174W in the insulin receptor (IR) gene. Clin Endocrinol (Oxf) 2009; 71:659-65. [PMID: 19170714 DOI: 10.1111/j.1365-2265.2009.03525.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Mutations in the insulin receptor (IR) gene are known to cause severe insulin resistance. Although clinical features due to a mutation can be diverse, hypoglycaemia is found in some cases. A family with a female proband diagnosed with type A insulin resistance syndrome was studied. Clinical characteristics were compared with the Arginine1174Glutamine (R1174N) mutation reported in the literature. METHODS The proband was a 16-year-old girl who was presented with intermittent hypoglycaemia, hirsutism, darkened skin, acne and oligomenorrhoea. A 5-h oral glucose tolerance test (OGTT), intravenous glucose tolerance test and continuous glucose monitoring system were performed for evaluation of glucose metabolism and insulin secretion. Results from a hyperinsulinaemic euglycaemic clamp on the proband were compared to nine normal glucose tolerance (NGT) controls. The IR gene of the proband, along with her parents and two dizygotic twin brothers were scanned for mutations by direct sequencing. RESULTS Elevated serum insulin and insulin : C-peptide ratios were found in the proband, the father and one of the twin brothers, carried a heterozygous missense mutation of Arginine1174Tryptophan (R1174W) in exon20 of the IR gene. The clamp study showed that the nonoxidative glucose disposal rates of the proband were near zero, and that the metabolic clearance rate for insulin was markedly reduced. CONCLUSIONS R1174 of the IR gene may be a candidate locus for hyperinsulinaemic hypoglycaemia. Clinical heterogeneity is not uncommon within families as well as among mutation carriers with different amino acid replacements. More pedigrees and long-term follow-up data are needed to document the evolution of beta-cell function and clarify the role of R1174 on insulin resistance and hyperinsulinaemic hypoglycaemia.
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Affiliation(s)
- Zhimin Huang
- Department of Endocrinology and Diabetes Centre, The First Affiliated Hospital of Sun Yat-sen University, #58 Zhongshan Er Road, Guangzhou, Guangdong, P.R. China
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Thiel CT, Knebel B, Knerr I, Sticht H, Müller-Wieland D, Zenker M, Reis A, Dörr HG, Rauch A. Two novel mutations in the insulin binding subunit of the insulin receptor gene without insulin binding impairment in a patient with Rabson-Mendenhall syndrome. Mol Genet Metab 2008; 94:356-62. [PMID: 18411068 DOI: 10.1016/j.ymgme.2008.02.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2008] [Revised: 02/29/2008] [Accepted: 02/29/2008] [Indexed: 01/31/2023]
Abstract
Homozygous or compound heterozygous mutations within the insulin binding domain of the human insulin receptor (INSR) are usually associated with severe impairment of insulin binding leading to Donohue syndrome ("Leprechaunism"), which is characterized by excessive hyperglycemia with hyperinsulinism, pre- and postnatal growth retardation, distinct dysmorphism and early death. Missense mutations in the beta subunits are commonly associated with a milder impairment of insulin binding and milder phenotype with prolonged survival and less dysmorphism, the so called Rabson-Mendenhall syndrome. We report on a 13-year-old girl with Donohue syndrome like dysmorphism, hyperinsulinism and prolonged survival due to two novel INSR missense mutations within the insulin binding domain. Unexpectedly, insulin binding assays and investigations of activation of central insulin signaling pathways in fibroblasts revealed no significant alterations. Instead, immunofluorescence studies showed abnormal perinuclear distribution of the INSR alpha and beta subunits. Our data indicate that the quality of insulin binding activity is correlated with survival, not with the dysmorphic phenotype, and it is not always a valid parameter for predicting INSR mutations as proposed.
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Affiliation(s)
- Christian T Thiel
- Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 10, D-91054 Erlangen, Germany.
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Abstract
Both type 2 diabetes mellitus (T2DM) and insulin resistance are complex traits in which multiple gene effects and metabolic and environmental factors combine to contribute to the overall pathogenesis of these conditions. This complexity has complicated the search for susceptibility genes and has led to different but complementary approaches being used for the detection of gene effects. These include the study of monogenic cases of insulin resistance and T2DM, association studies of candidate genes and genome-wide scans. The peroxisome proliferator-activated receptor gamma (PPARgamma) and calpain-10 (CAPN10) genes have recently been identified as T2DM susceptibility genes, and the lessons learnt from these studies are helping to shape future strategies to search for additional susceptibility genes in T2DM and insulin resistance.
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Affiliation(s)
- E A McIntyre
- School of Clinical Medical Sciences, University of Newcastle upon Tyne, UK
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Recién nacido con hiperglucemia persistente e hiperinsulinemia. An Pediatr (Barc) 2001. [DOI: 10.1016/s1695-4033(01)77573-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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