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Ding Y, Cheng M, Cao B, Liu M, Hu X, Wu D. Case report: Clinical characteristics and Genetical analysis of HSD11B2 in three Chinese children with apparent mineralocorticoid excess: a case series. Front Endocrinol (Lausanne) 2025; 15:1491825. [PMID: 39931437 PMCID: PMC11807828 DOI: 10.3389/fendo.2024.1491825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 12/23/2024] [Indexed: 02/13/2025] Open
Abstract
Background Apparent Mineralocorticoid Excess (AME) is a rare autosomal recessive disorder, characterized by a notably complex diagnostic process. To date, the majority of documented cases have been presented as individual case reports. This article aims to enhance the understanding of the course and prognosis of AME, by detailing the management protocols employed for patients with genetically confirmed diagnoses. Methods An analysis comprising three cases and a review of relevant literature were conducted to synthesize the insights and experiences derived from gathering clinical and laboratory data on patients. Results All three patients were born to non-consanguineous parents, were small for gestational age and exhibited severe hypokalemia, metabolic alkalosis, hypertension, nephrocalcinosis, and hypercalciuria. The glomerular filtration rate was normal in all cases. One patient experienced complications related to hypertension. Genetic analysis revealed biallelic recessive variations in the HSD11B2 gene in all three patients. Treatment with oral spironolactone and potassium chloride resulted in the normalization of both blood pressure and serum potassium levels in all patients. Conclusion This study presents the diagnostic and treatment experiences of three Chinese pediatric patients with AME type I. Through our analysis, four novel variants of the HSD11B2 gene were identified, thereby enhancing the genotype-phenotype spectrum associated with AME. Early genetic testing in patients suspected of having AME is beneficial for facilitating prompt diagnosis and the implementation of standardized treatment protocols. Such measures are essential for the prevention or mitigation of target organ damage, as well as for the reduction of associated morbidity and mortality.
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Affiliation(s)
- Yuan Ding
- Department of Endocrinology, Genetics, Metabolism, Beijing Children’s Hospital, Capital Medical University, National Centre for Children’s Health, Beijing, China
- Ministry of Education (MOE) Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Ming Cheng
- Department of Endocrinology, Genetics, Metabolism, Beijing Children’s Hospital, Capital Medical University, National Centre for Children’s Health, Beijing, China
- Ministry of Education (MOE) Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Bingyan Cao
- Department of Endocrinology, Genetics, Metabolism, Beijing Children’s Hospital, Capital Medical University, National Centre for Children’s Health, Beijing, China
- Ministry of Education (MOE) Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Min Liu
- Department of Endocrinology, Genetics, Metabolism, Beijing Children’s Hospital, Capital Medical University, National Centre for Children’s Health, Beijing, China
- Ministry of Education (MOE) Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Xuyun Hu
- Ministry of Education (MOE) Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Di Wu
- Department of Endocrinology, Genetics, Metabolism, Beijing Children’s Hospital, Capital Medical University, National Centre for Children’s Health, Beijing, China
- Ministry of Education (MOE) Key Laboratory of Major Diseases in Children, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
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Lu YT, Zhang D, Zhang QY, Zhou ZM, Yang KQ, Zhou XL, Peng F. Apparent mineralocorticoid excess: comprehensive overview of molecular genetics. J Transl Med 2022; 20:500. [PMID: 36329487 PMCID: PMC9632093 DOI: 10.1186/s12967-022-03698-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 09/17/2022] [Accepted: 10/09/2022] [Indexed: 11/06/2022] Open
Abstract
Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11β-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.
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Affiliation(s)
- Yi-Ting Lu
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Di Zhang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiong-Yu Zhang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ze-Ming Zhou
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kun-Qi Yang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xian-Liang Zhou
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Fan Peng
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Attention deficit hyperactivity disorder among children related to maternal job stress during pregnancy in Taiwan: a prospective cohort study. Int Arch Occup Environ Health 2022; 95:1231-1241. [PMID: 34999998 DOI: 10.1007/s00420-021-01821-9] [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: 09/06/2021] [Accepted: 11/25/2021] [Indexed: 11/05/2022]
Abstract
OBJECTIVE Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorders. Although studies have suggested relationships between ADHD in children and maternal psychosocial stress during pregnancy, little is known about the effects of work-related mental stress. Considering the increasing number of pregnant women who continue to work during the gestation period, this study investigated whether work-related stress during pregnancy is related to offspring ADHD. METHODS The Taiwan Birth Cohort Study followed selected representative mother-infant pairs in a face-to-face interview since a child was 6 months old. A total of 10,556 working pregnant women who completed follow-up 8 years later were included. Whether the 8-year-old child had ever received a diagnosis of ADHD were inquired. Self-reported job stress during pregnant period was obtained 6 months after delivery. Factors including perinatal and socioeconomic factors as well as the mother's job conditions were further analyzed with logistic regression. RESULTS Among those who continued working during pregnancy, 3850 (36.5%) mothers reported having job stress during pregnancy, and 210 (2.0%) of the children were diagnosed as having ADHD before 8 years of age. Compared with mothers who reported no job stress, the adjusted odds ratio of child ADHD was 1.91 (95% CI 1.21-3.07) for mothers with "very stressful" jobs during pregnancy and 1.53 (95% CI 1.04-2.25) for mothers with "rather stressful" jobs. CONCLUSION Among pregnant female workers, higher levels of job stress were related to the higher occurrence of ADHD in their children.
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Fan P, Lu YT, Yang KQ, Zhang D, Liu XY, Tian T, Luo F, Wang LP, Ma WJ, Liu YX, Zhang HM, Song L, Cai J, Lou Y, Zhou XL. Apparent mineralocorticoid excess caused by novel compound heterozygous mutations in HSD11B2 and characterized by early-onset hypertension and hypokalemia. Endocrine 2020; 70:607-615. [PMID: 32816205 PMCID: PMC7674368 DOI: 10.1007/s12020-020-02460-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 08/08/2020] [Indexed: 11/22/2022]
Abstract
PURPOSE Apparent mineralocorticoid excess (AME) is an ultrarare autosomal recessive disorder resulting from deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) caused by mutations in HSD11B2. The purpose of this study was to identify novel compound heterozygous HSD11B2 mutations in a Chinese pedigree with AME and conduct a systematic review evaluating the AME clinical features associated with HSD11B2 mutations. METHODS Next-generation sequencing was performed in the proband, and Sanger sequencing was used to identify candidate variants in family members, 100 hypertensives, and 100 healthy controls. A predicted structure of 11βHSD2 was constructed by in silico modeling. A systematic review was used to identify cases of HSD11B2-related AME. Data for genotyping and clinical characterizations and complications were extracted. RESULTS Next-generation sequencing showed novel compound heterozygous mutations (c.343_348del and c.1099_1101del) in the proband with early-onset hypertension and hypokalemia. Sanger sequencing verified the monoallelic form of the same mutations in five other relatives but not in 100 hypertensives or 100 healthy subjects. In silico structural modeling showed that compound mutations may simultaneously perturb the substrate and coenzyme binding pocket. A systematic review of 101 AME patients with 54 HSD11B2 mutations revealed early-onset hypertension, hypokalemia and homozygous mutations as common features. The homozygous HSD11B2 mutations correlated with low birth weight (r = 0.285, P = 0.02). CONCLUSIONS We report novel compound heterozygous HSD11B2 mutations in a Chinese teenager with early-onset hypertension, and enriched genotypic and phenotypic spectrums in AME. Genetic testing helps early diagnosis and treatment for AME patients, which may avoid target organ damage.
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Affiliation(s)
- Peng Fan
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi-Ting Lu
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kun-Qi Yang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Di Zhang
- Emergency and Critical Care Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xue-Ying Liu
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Tian
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fang Luo
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin-Ping Wang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wen-Jun Ma
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ya-Xin Liu
- Emergency and Critical Care Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hui-Min Zhang
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Song
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Cai
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Lou
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Xian-Liang Zhou
- Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Bertulli C, Hureaux M, De Mutiis C, Pasini A, Bockenhauer D, Vargas-Poussou R, La Scola C. A Rare Cause of Chronic Hypokalemia with Metabolic Alkalosis: Case Report and Differential Diagnosis. CHILDREN-BASEL 2020; 7:children7110212. [PMID: 33167351 PMCID: PMC7694404 DOI: 10.3390/children7110212] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/08/2020] [Accepted: 10/28/2020] [Indexed: 11/16/2022]
Abstract
Hypokalemia and metabolic alkalosis can be present in different rare diseases, and the differential diagnosis of these forms is challenging. Apparent mineralcorticoid (AME) excess syndrome is one of these conditions. Characterized by increased blood pressure due to excessive sodium retention and plasma volume, it is caused by a mutation in the HSD11B2 gene encoding the oxydoreductase enzyme 11β-hydroxysteroide dehydrogenase type 2. We report the case of a child presenting with failure to thrive associated with early detection of hypokalemia, metabolic alkalosis, nephrocalcinosis and hypertension in which AME syndrome was detected. A novel mutation in the HSD11B2 gene was identified in this patient. In clinical pictures characterized by metabolic alkalosis and hypokalemia, the evaluation of renin, aldosterone and blood pressure is crucial for accurate diagnosis. AME syndrome is a rare disorder that can be an insidious but lethal disease, if untreated. With clinical signs appearing during the first days of life. Early diagnosis is imperative in order to enable prompt and adequate treatment to improve the outcome of these patients.
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Affiliation(s)
- Cristina Bertulli
- Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliero Universitaria Sant’Orsola-Malpighi, 40138 Bologna, Italy; (C.B.); (C.D.M.); (A.P.)
| | - Marguerite Hureaux
- Assistance Publique Hôpitaux de Paris, Department of Genetics, Hôpital Européen Georges-Pompidou, 75015 Paris, France; (M.H.); (R.V.-P.)
| | - Chiara De Mutiis
- Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliero Universitaria Sant’Orsola-Malpighi, 40138 Bologna, Italy; (C.B.); (C.D.M.); (A.P.)
| | - Andrea Pasini
- Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliero Universitaria Sant’Orsola-Malpighi, 40138 Bologna, Italy; (C.B.); (C.D.M.); (A.P.)
| | - Detlef Bockenhauer
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK;
- Department of Renal Medicine, University College London, London WC1E 6BT, UK
| | - Rosa Vargas-Poussou
- Assistance Publique Hôpitaux de Paris, Department of Genetics, Hôpital Européen Georges-Pompidou, 75015 Paris, France; (M.H.); (R.V.-P.)
| | - Claudio La Scola
- Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliero Universitaria Sant’Orsola-Malpighi, 40138 Bologna, Italy; (C.B.); (C.D.M.); (A.P.)
- Correspondence:
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Carvajal CA, Tapia-Castillo A, Vecchiola A, Baudrand R, Fardella CE. Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome. J Clin Endocrinol Metab 2020; 105:5691192. [PMID: 31909799 DOI: 10.1210/clinem/dgz315] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/28/2019] [Indexed: 02/13/2023]
Abstract
CONTEXT Arterial hypertension (AHT) is one of the most frequent pathologies in the general population. Subtypes of essential hypertension characterized by low renin levels allowed the identification of 2 different clinical entities: aldosterone-mediated mineralocorticoid receptor (MR) activation and cortisol-mediated MR activation. EVIDENCE ACQUISITION This review is based upon a search of Pubmed and Google Scholar databases, up to August 2019, for all publications relating to endocrine hypertension, apparent mineralocorticoid excess (AME) and cortisol (F) to cortisone (E) metabolism. EVIDENCE SYNTHESIS The spectrum of cortisol-mediated MR activation includes the classic AME syndrome to milder (nonclassic) forms of AME, the latter with a much higher prevalence (7.1%) than classic AME but different phenotype and genotype. Nonclassic AME (NC-AME) is mainly related to partial 11βHSD2 deficiency associated with genetic variations and epigenetic modifications (first hit) and potential additive actions of endogenous or exogenous inhibitors (ie, glycyrrhetinic acid-like factors [GALFS]) and other factors (ie, age, high sodium intake) (second hit). Subjects with NC-AME are characterized by a high F/E ratio, low E levels, normal to elevated blood pressure, low plasma renin and increased urinary potassium excretion. NC-AME condition should benefit from low-sodium and potassium diet recommendations and monotherapy with MR antagonists. CONCLUSION NC-AME has a higher prevalence and a milder phenotypical spectrum than AME. NC-AME etiology is associated to a first hit (gene and epigene level) and an additive second hit. NC-AME subjects are candidates to be treated with MR antagonists aimed to improve blood pressure, end-organ damage, and modulate the renin levels.
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Affiliation(s)
- Cristian A Carvajal
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII-ICM), Santiago, Chile
- Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Alejandra Tapia-Castillo
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII-ICM), Santiago, Chile
- Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Andrea Vecchiola
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII-ICM), Santiago, Chile
- Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Rene Baudrand
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Carlos E Fardella
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII-ICM), Santiago, Chile
- Centro Traslacional de Endocrinología UC (CETREN), Pontificia Universidad Catolica de Chile, Santiago, Chile
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Horri-Naceur A, Timson DJ. In Silico Analysis of the Effects of Point Mutations on α-Globin: Implications for α-Thalassemia. Hemoglobin 2020; 44:89-103. [PMID: 32420790 DOI: 10.1080/03630269.2020.1739067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Hemoglobinopathies are inherited diseases that impair the structure and function of the oxygen-carrying pigment hemoglobin (Hb). Adult Hb consists of two α and two β subunits. α-Thalassemia (α-thal) affects the genes that code for the α-globin chains, HBA1 and HBA2. Mutations can result in asymptomatic, mild or severe outcomes depending on several factors, such as mutation type, number of mutations and the location at which they occur. PredictSNP was used to estimate whether every possible single nucleotide polymorphism (SNP) would have a neutral or deleterious effect on the protein. These results were then used to create a plot of predicted tolerance to change for each residue in the protein. Tolerance to change was negatively correlated with the residue's sequence conservation score. The PredictSNP data were compared to clinical reports of 110 selected variants in the literature. There were 29 disagreements between the two data types. Some of these could be resolved by considering the role of the affected residue in binding other molecules. The three-dimensional structures of some of these variant proteins were modeled. These models helped explain variants which affect heme binding. We predict that where a point mutation alters a residue that is intolerant to change, is well conserved and or involved in interactions, it is likely to be associated with disease. Overall, the data from this study could be used alongside biochemical and clinical data to assess novel α-globin variants.
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Affiliation(s)
- Agathe Horri-Naceur
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, East Sussex, UK
| | - David J Timson
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, East Sussex, UK
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Porntadavity S, Jeenduang N. Structure–Function Relationships of LDL Receptor Missense Mutations Using Homology Modeling. Protein J 2019; 38:447-462. [DOI: 10.1007/s10930-019-09860-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Tapia-Castillo A, Baudrand R, Vaidya A, Campino C, Allende F, Valdivia C, Vecchiola A, Lagos CF, Fuentes CA, Solari S, Martínez-Aguayo A, García H, Carvajal CA, Fardella CE. Clinical, Biochemical, and Genetic Characteristics of "Nonclassic" Apparent Mineralocorticoid Excess Syndrome. J Clin Endocrinol Metab 2019; 104:595-603. [PMID: 30239803 DOI: 10.1210/jc.2018-01197] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 09/10/2018] [Indexed: 11/19/2022]
Abstract
CONTEXT Classical apparent mineralocorticoid excess (AME) is a rare recessive disorder, caused by severe 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) deficiency. AME manifests as low-renin pediatric hypertension, hypokalemia and high cortisol/cortisone (F/E) ratio. OBJECTIVE To evaluate nonclassic AME (NC-AME) due to partial 11β-HSD2 insufficiency and its association with hypertension, mineralocorticoid receptor (MR) activation, and inflammatory parameters. DESIGN Cross-sectional study. SETTING Primary care cohort. PARTICIPANTS We recruited 127 adolescents and adults. Subjects with secondary hypertension were excluded. We measured clinical, biochemical, renal, vascular, and inflammatory variables. Sequencing of HSD11B2 gene was performed in all subjects. MAIN OUTCOME MEASURE NC-AME. RESULTS Serum F/E ratio was positively associated with systolic blood pressure (BP), microalbuminuria, and high-sensitivity C-reactive protein (hs-CRP). Serum cortisone correlated with MR activation parameters even when adjusted for age, body mass index, and sex: lower cortisone with higher potassium excretion (partial r = -0.29, P = 0.002) and with lower plasma renin activity (PRA) (partial r = 0.29, P = 0.001). Consistently, we identified 9 in 127 subjects (7.1%) with high F/E ratios (first quartile) and low cortisone (last quartile), suggestive of NC-AME. These subjects had higher systolic BP, 141.4 ± 25.7 mm Hg vs 127.3 ± 18.1 mm Hg, P = 0.03; lower PRA, 0.36 ± 0.19 ng/L*s vs 0.64 ± 0.47 ng/L*s, P < 0.0001; and greater potassium excretion, microalbuminuria, hs-CRP, and plasminogen activator inhibitor. We only found in 2 out of 9 subjects with NC-AME heterozygous mutations in the HSD11B2 gene. CONCLUSIONS These findings suggest a spectrum of partial 11β-HSD2 insufficiency in a primary care cohort without the classic phenotype and genotype of AME. NC-AME may represent a phenotype of MR activation and cardiovascular risk, suggesting that these subjects could be treated with MR antagonists.
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Affiliation(s)
- Alejandra Tapia-Castillo
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Center for Genetics and Genomics, School of Medicine, Clínica Alemana-Universidad del Desarrollo, Lo Barnechea, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
| | - Rene Baudrand
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Anand Vaidya
- Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Carmen Campino
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
| | - Fidel Allende
- Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carolina Valdivia
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Andrea Vecchiola
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
| | - Carlos F Lagos
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
- Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Cristóbal A Fuentes
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Sandra Solari
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Campus Los Leones, Santiago, Chile
| | - Alejandro Martínez-Aguayo
- Endocrinology Pediatrics Division, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Hernán García
- Endocrinology Pediatrics Division, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Cristian A Carvajal
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
| | - Carlos E Fardella
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
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Mancha‐Ramirez AM, Yang X, Liang H, Junco J, Lee KP, Bovio SF, Espinoza M, Wool J, Slaga A, Glade DC, Hanes M, Malik G, Kim DJ, DiGiovanni J, Slaga TJ. Harnessing the gatekeepers of glucocorticoids for chemoprevention of non-melanoma skin cancer. Mol Carcinog 2019; 58:102-112. [PMID: 30302860 PMCID: PMC6563487 DOI: 10.1002/mc.22912] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 09/08/2018] [Accepted: 09/10/2018] [Indexed: 11/11/2022]
Abstract
Despite effective surgical methods for non-melanoma skin cancer (NMSC), patients suffer from tissue damage, scarring, or even disfigurement; thus, there is a need for chemopreventive approaches. Because of the complex interplay between glucocorticoids (GCs), inflammation, and cancer, we sought to determine the role of 11β-hydroxysteroid dehydrogenase 1 and 2 (11βHSD1 and 2) in regulating GCs during skin cancer development and progression. 11βHSDs modulate the activation of GCs in a tissue-specific manner and have been reported to play a role in development and progression of other types of cancer, but their role has not yet been reported in NMSC. Here, we found a significant upregulation of 11βHSD2 protein in skin cancer cells when compared to normal skin cells, suggesting a role for this enzyme in the multifactorial process of skin cancer development. In addition, inhibition of 11βHSD2 with siRNA resulted in significant reduction in colony formation in vitro. Finally, our in vivo study elucidated that inhibition of 11βHSD2 with pharmacological inhibitor, Glycyrrhetinic acid (GA) could significantly diminish tumorigenesis in a well-studied in vivo mouse model of NMSC. Overall, these studies highlight for the first time a potential novel role for 11βHSD2 in NMSC development and may allow for new GC treatment approaches capable of avoiding deactivation by the enzyme. If 11βHSD2 can be inhibited as we have done here, or circumvented using modified GCs, this may lead to more efficacious outcomes for NMSC patients by preventing deactivation of the GC and minimizing resistance.
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Affiliation(s)
- Anna M. Mancha‐Ramirez
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Xiaoyu Yang
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Huiyun Liang
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Jacob Junco
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Kevin P. Lee
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Sarah F. Bovio
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Maricruz Espinoza
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Julia Wool
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Andrew Slaga
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Daniel C. Glade
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Martha Hanes
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Gunjan Malik
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
| | - Dae Joon Kim
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
- Department of Biomedical SciencesSchool of MedicineThe University of Texas Rio Grande ValleyEdinburgTexas
| | - John DiGiovanni
- College of PharmacyThe University of Texas at AustinAustinTexas
| | - Thomas J. Slaga
- Department of PharmacologyThe University of Texas Health Science Center at San AntonioSan AntonioTexas
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Carvajal CA, Tapia-Castillo A, Valdivia CP, Allende F, Solari S, Lagos CF, Campino C, Martínez-Aguayo A, Vecchiola A, Pinochet C, Godoy C, Iturrieta V, Baudrand R, Fardella CE. Serum Cortisol and Cortisone as Potential Biomarkers of Partial 11β-Hydroxysteroid Dehydrogenase Type 2 Deficiency. Am J Hypertens 2018; 31:910-918. [PMID: 29617893 DOI: 10.1093/ajh/hpy051] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 03/29/2018] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Pathogenic variations in HSD11B2 gene triggers the apparent mineralocorticoid excess syndrome (AME). There is scarce information regarding the phenotypes of subjects carrying heterozygous pathogenic variants in HSD11B2 gene. We investigated if serum cortisol/cortisone (F/E) ratio and cortisone are useful for identifying partial 11βHSD2 deficiency in those heterozygous subjects. METHODS We studied two patients diagnosed with AME and their families carrying either D223N or R213C mutation. We also evaluated 32 healthy control subjects (13 children and 19 adults) to obtain normal references ranges for all measured variables. Case 1: A boy carrying D223N mutation in HSD11B2 gene and Case 2: A girl carrying R213C mutation. We assessed serum F/E ratio and cortisone by HPLC-MS/MS, aldosterone, plasma-renin-activity(PRA), electrolytes, and HSD11B2 genetic analyses. RESULTS The normal values (median [interquartile range]) in children for serum F/E and cortisone (µg/dl) were 2.56 [2.21-3.69] and 2.54 [2.35-2.88], and in adults were 4.42 [3.70-4.90] and 2.23 [1.92-2.57], respectively. Case 1 showed a very high serum F/E 28.8 and low cortisone 0.46 µg/dl. His mother and sister were normotensives and heterozygous for D223N mutation with high F/E (13.2 and 6.0, respectively) and low cortisone (2.0 and 2.2, respectively). Case 2 showed a very high serum F/E 175 and suppressed cortisone 0.11 µg/dl. Her parents and sister were heterozygous for the R213C mutation with normal phenotype, but high F/E and low cortisone. Heterozygous subjects showed normal aldosterone, PRA, but lower fractional excretion of sodium and urinary Na/K ratio than controls. CONCLUSION Serum F/E ratio and cortisone allow to identify partial 11βHSD2 deficiencies, as occurs in heterozygous subjects, who would be susceptible to develop arterial hypertension.
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Affiliation(s)
- Cristian A Carvajal
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
| | - Alejandra Tapia-Castillo
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
- Faculty of Medicine, Universidad del Desarrollo, Santiago, Chile
| | - Carolina P Valdivia
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Fidel Allende
- Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Sandra Solari
- Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carlos F Lagos
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
- Facultad de Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Carmen Campino
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
| | - Alejandro Martínez-Aguayo
- Endocrinology Pediatrics Division, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Andrea Vecchiola
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
| | - Constanza Pinochet
- Endocrinology Pediatrics Division, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Claudia Godoy
- Endocrinology Pediatrics Division, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Virginia Iturrieta
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rene Baudrand
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Carlos E Fardella
- Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy (IMII), Santiago, Chile
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12
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Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency. Proc Natl Acad Sci U S A 2017; 114:E11248-E11256. [PMID: 29229831 DOI: 10.1073/pnas.1716621115] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Mutations in 11β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) cause an extraordinarily rare autosomal recessive disorder, apparent mineralocorticoid excess (AME). AME is a form of low renin hypertension that is potentially fatal if untreated. Mutations in the HSD11B2 gene result either in severe AME or a milder phenotype (type 2 AME). To date, ∼40 causative mutations have been identified. As part of the International Consortium for Rare Steroid Disorders, we have diagnosed and followed the largest single worldwide cohort of 36 AME patients. Here, we present the genotype and clinical phenotype of these patients, prominently from consanguineous marriages in the Middle East, who display profound hypertension and hypokalemic alkalosis. To correlate mutations with phenotypic severity, we constructed a computational model of the HSD11B2 protein. Having used a similar strategy for the in silico evaluation of 150 mutations of CYP21A2, the disease-causing gene in congenital adrenal hyperplasia, we now provide a full structural explanation for the clinical severity of AME resulting from each known HSD11B2 missense mutation. We find that mutations that allow the formation of an inactive dimer, alter substrate/coenzyme binding, or impair structural stability of HSD11B2 yield severe AME. In contrast, mutations that cause an indirect disruption of substrate binding or mildly alter intramolecular interactions result in type 2 AME. A simple in silico evaluation of novel missense mutations could help predict the often-diverse phenotypes of an extremely rare monogenic disorder.
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13
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Jiménez-Canino R, Lorenzo-Díaz F, Odermatt A, Bailey MA, Livingstone DEW, Jaisser F, Farman N, Alvarez de la Rosa D. 11β-HSD2 SUMOylation Modulates Cortisol-Induced Mineralocorticoid Receptor Nuclear Translocation Independently of Effects on Transactivation. Endocrinology 2017; 158:4047-4063. [PMID: 28938454 DOI: 10.1210/en.2017-00440] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 09/12/2017] [Indexed: 12/26/2022]
Abstract
The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) has an essential role in aldosterone target tissues, conferring aldosterone selectivity for the mineralocorticoid receptor (MR) by converting 11β-hydroxyglucocorticoids to inactive 11-ketosteroids. Congenital deficiency of 11β-HSD2 causes a form of salt-sensitive hypertension known as the syndrome of apparent mineralocorticoid excess. The disease phenotype, which ranges from mild to severe, correlates well with reduction in enzyme activity. Furthermore, polymorphisms in the 11β-HSD2 coding gene (HSD11B2) have been linked to high blood pressure and salt sensitivity, major cardiovascular risk factors. 11β-HSD2 expression is controlled by different factors such as cytokines, sex steroids, or vasopressin, but posttranslational modulation of its activity has not been explored. Analysis of 11β-HSD2 sequence revealed a consensus site for conjugation of small ubiquitin-related modifier (SUMO) peptide, a major posttranslational regulatory event in several cellular processes. Our results demonstrate that 11β-HSD2 is SUMOylated at lysine 266. Non-SUMOylatable mutant K266R showed slightly higher substrate affinity and decreased Vmax, but no effects on protein stability or subcellular localization. Despite mild changes in enzyme activity, mutant K266R was unable to prevent cortisol-dependent MR nuclear translocation. The same effect was achieved by coexpression of wild-type 11β-HSD2 with sentrin-specific protease 1, a protease that catalyzes SUMO deconjugation. In the presence of 11β-HSD2-K266R, increased nuclear MR localization did not correlate with increased response to cortisol or increased recruitment of transcriptional coregulators. Taken together, our data suggests that SUMOylation of 11β-HSD2 at residue K266 modulates cortisol-mediated MR nuclear translocation independently of effects on transactivation.
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Affiliation(s)
- Rubén Jiménez-Canino
- Department of Basic Medical Sciences, Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, Universidad de La Laguna, 38200 Tenerife, Spain
| | - Fabián Lorenzo-Díaz
- Department of Basic Medical Sciences, Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, Universidad de La Laguna, 38200 Tenerife, Spain
| | - Alex Odermatt
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056 Basel, Switzerland
| | - Matthew A Bailey
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom
| | - Dawn E W Livingstone
- British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom
| | - Frederic Jaisser
- INSERM UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 75006 Paris, France
| | - Nicolette Farman
- INSERM UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 75006 Paris, France
| | - Diego Alvarez de la Rosa
- Department of Basic Medical Sciences, Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, Universidad de La Laguna, 38200 Tenerife, Spain
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In silico prediction of the effects of mutations in the human triose phosphate isomerase gene: Towards a predictive framework for TPI deficiency. Eur J Med Genet 2017; 60:289-298. [PMID: 28341520 DOI: 10.1016/j.ejmg.2017.03.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 02/27/2017] [Accepted: 03/20/2017] [Indexed: 01/24/2023]
Abstract
Triose phosphate isomerase (TPI) deficiency is a rare, but highly debilitating, inherited metabolic disease. Almost all patients suffer severe neurological effects and the most severely affected are unlikely to live beyond early childhood. Here, we describe an in silico study into well-characterised variants which are associated with the disease alongside an investigation into 79 currently uncharacterised TPI variants which are known to occur in the human population. The majority of the disease-associated mutations affected amino acid residues close to the dimer interface or the active site. However, the location of the altered amino acid residue did not predict the severity of the resulting disease. Prediction of the effect on protein stability using a range of different programs suggested a relationship between the degree of instability caused by the sequence variation and the severity of the resulting disease. Disease-associated variations tended to affect well-conserved residues in the protein's sequence. However, the degree of conservation of the residue was not predictive of disease severity. The majority of the 79 uncharacterised variants are potentially associated with disease since they were predicted to destabilise the protein and often occur in well-conserved residues. We predict that individuals homozygous for the corresponding mutations would be likely to suffer from TPI deficiency.
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15
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Browne C, Timson DJ. In SilicoPrediction of the Effects of Mutations in the Human Mevalonate Kinase Gene: Towards a Predictive Framework for Mevalonate Kinase Deficiency. Ann Hum Genet 2015; 79:451-9. [DOI: 10.1111/ahg.12126] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 04/29/2015] [Accepted: 05/21/2015] [Indexed: 11/30/2022]
Affiliation(s)
- Claire Browne
- School of Biological Sciences; Queen's University Belfast, Medical Biology Centre; 97 Lisburn Road Belfast BT9 7BL UK
| | - David J. Timson
- School of Biological Sciences; Queen's University Belfast, Medical Biology Centre; 97 Lisburn Road Belfast BT9 7BL UK
- Institute for Global Food Security; Queen's University Belfast; 18-30 Malone Road Belfast BT9 5BN UK
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16
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Timson DJ. Value of predictive bioinformatics in inherited metabolic diseases. World J Med Genet 2015; 5:46-51. [DOI: 10.5496/wjmg.v5.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 04/28/2015] [Accepted: 05/18/2015] [Indexed: 02/06/2023] Open
Abstract
Typically, inherited metabolic diseases arise from point mutations in genes encoding metabolic enzymes. Although some of these mutations directly affect amino acid residues in the active sites of these enzymes, the majority do not. It is now well accepted that the majority of these disease-associated mutations exert their effects through alteration of protein stability, which causes a reduction in enzymatic activity. This finding suggests a way to predict the severity of newly discovered mutations. In silico prediction of the effects of amino acid sequence alterations on protein stability often correlates with disease severity. However, no stability prediction tool is perfect and, in general, better results are obtained if the predictions from a variety of tools are combined and then interpreted. In addition to predicted alterations to stability, the degree of conservation of a particular residue can also be a factor which needs to be taken into account: alterations to highly conserved residues are more likely to be associated with severe forms of the disease. The approach has been successfully applied in a variety of inherited metabolic diseases, but further improvements are necessary to enable robust translation into clinically useful tools.
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17
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Structural comparison, substrate specificity, and inhibitor binding of AGPase small subunit from monocot and dicot: present insight and future potential. BIOMED RESEARCH INTERNATIONAL 2014; 2014:583606. [PMID: 25276800 PMCID: PMC4167649 DOI: 10.1155/2014/583606] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/08/2014] [Accepted: 04/21/2014] [Indexed: 11/18/2022]
Abstract
ADP-glucose pyrophosphorylase (AGPase) is the first rate limiting enzyme of starch biosynthesis pathway and has been exploited as the target for greater starch yield in several plants. The structure-function analysis and substrate binding specificity of AGPase have provided enormous potential for understanding the role of specific amino acid or motifs responsible for allosteric regulation and catalytic mechanisms, which facilitate the engineering of AGPases. We report the three-dimensional structure, substrate, and inhibitor binding specificity of AGPase small subunit from different monocot and dicot crop plants. Both monocot and dicot subunits were found to exploit similar interactions with the substrate and inhibitor molecule as in the case of their closest homologue potato tuber AGPase small subunit. Comparative sequence and structural analysis followed by molecular docking and electrostatic surface potential analysis reveal that rearrangements of secondary structure elements, substrate, and inhibitor binding residues are strongly conserved and follow common folding pattern and orientation within monocot and dicot displaying a similar mode of allosteric regulation and catalytic mechanism. The results from this study along with site-directed mutagenesis complemented by molecular dynamics simulation will shed more light on increasing the starch content of crop plants to ensure the food security worldwide.
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18
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Alzahrani AS, Aljuhani N, Qasem E, Almohanna M, Hamoudh E, AlOmair A, Alharbi N. Apparent Mineralocorticoid Excess Caused by a Novel Mutation in 11-β Hydroxysteroid Dehydrogenase Type 2 Enzyme: Its Genetics and Response to Therapy. Endocr Pract 2014; 20:e151-6. [PMID: 24936560 DOI: 10.4158/ep14094.cr] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To present a case of apparent mineralocorticoid excess (AME) due to a novel mutation in the HSD11B2 gene and describe the patient's response to therapy. METHODS The clinical, biochemical, and genetic features of the proband and his family are presented. For the genetic study, DNA was extracted from peripheral leucocytes. The exons and exon-intron boundaries were polymerase chain reaction (PCR)-amplified and directly sequenced. RESULTS A 10-year-old male presented with hypertension (HTN) and weakness and was found to have hypokalemia of 2.6 mmol/L. Plasma renin was undetectable, and plasma and urinary aldosterone were low. Serum cortisol and deoxycorticosterone were normal. Daily urinary excretion of cortisol was normal, but urinary and serum cortisone levels were undetectable. The patient was treated with spiranolactone with inadequate response. A small dose of dexamethasone was added and led to excellent control of HTN and hypokalemia. Genetic studies showed a novel missense biallelic mutation changing guanine to adenine in exon 3 (c.G526A) of the HSD11B2. This mutation changes the amino acid aspartic acid to asparagine at codon 176 (p.D176N). A monoallelic form of the same mutation was found in the parents and 3 of his 4 healthy siblings but not in a healthy sister or 100 normal subjects. CONCLUSIONS A case of AME due to a novel mutation in HSD11B2 showed the usual features of AME but exhibited an inadequate response to spironolactone. A small dose of dexamethasone resulted in an excellent response.
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Affiliation(s)
- Ali S Alzahrani
- Department of Medicine, King Faisal Specialist Hospital & Research Center Department of Molecular Oncology, King Faisal Specialist Hospital & Research Center
| | | | - Ebtesam Qasem
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Center
| | - Mai Almohanna
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Center
| | - Eman Hamoudh
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Center
| | - Abeer AlOmair
- Department of Molecular Oncology, King Faisal Specialist Hospital & Research Center
| | - Naffaa Alharbi
- Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Jeddah
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19
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Ruan LL, Xu J, Wang CL, Zou CC. Variants of 11β-hydroxysteroid dehydrogenase (HSD11B) gene type 1 and 2 in Chinese obese adolescents. J Endocrinol Invest 2014; 37:565-73. [PMID: 24729284 DOI: 10.1007/s40618-014-0075-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 03/26/2014] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To investigate the relationship between 11β-hydroxysteroid dehydrogenase (HSD11B) gene type 1 and 2 and obesity in Chinese children. METHODS A total of 400 obese and 200 healthy adolescents were enrolled as obese and control groups. Seven SNPs in HSD11B1 (rs4393158, rs2235543, rs10082248, rs10863782, rs2236903, rs2298930, rs4545339) and four variants in HSD11B2 gene (rs28934592, rs28934591, rs28934594 and rs28934593) were measured by automated platform MassArray. RESULTS The rs28934592 in HSD11B2 and rs10863782 in HSD11B1 were excluded as false positive or HWE P < 0.05. Moreover, one allele type was found in the other three locations of HSD11B2. The minor allele frequency of rs2235543 and rs10082248 was higher in patients than that in controls (P = 0.045, P = 0.041, respectively). The rs10082248, rs2298930 and rs4545339 were associated with the risk of obesity in the recessive model (P < 0.05, respectively). Moreover, the total cholesterol in patients with GG or AG genotype was significantly higher than that in patients with AA genotype in rs10082248. The rs4393158 was associated with the hypertension in log-additive model test (P = 0.037), and glucose abnormal and hypercholesteremia in dominant model test (P < 0.05, respectively), while the rs2235543 was associated with hypercholesteremia in overdominant model test (P = 0.017). CONCLUSIONS The polymorphism of HSD11B1 may be a cause of childhood obesity, or even associated with the complication of childhood obesity. However, variants of HSD11B2 may be not a cause of obesity.
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Affiliation(s)
- Li Li Ruan
- Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine and The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, 57 Zhugan Xiang, Hangzhou, 310003, China,
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20
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Lagos CF, Vecchiola A, Allende F, Fuentes CA, Tichauer JE, Valdivia C, Solari S, Campino C, Tapia-Castillo A, Baudrand R, Villarroel P, Cifuentes M, Owen GI, Carvajal CA, Fardella CE. Identification of novel 11β-HSD1 inhibitors by combined ligand- and structure-based virtual screening. Mol Cell Endocrinol 2014; 384:71-82. [PMID: 24447464 DOI: 10.1016/j.mce.2014.01.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Revised: 12/15/2013] [Accepted: 01/09/2014] [Indexed: 10/25/2022]
Abstract
11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to cortisol in a NADPH dependent manner. Overexpression of 11β-HSD1 in key metabolic tissues is related to the development of type 2 diabetes, obesity, hypertension and metabolic syndrome. Using crystal structures of human 11β-HSD1 in complex with inhibitors as source of structural information, a combined ligand and structure-based virtual screening approach was implemented to identify novel 11β-HSD1 inhibitors. A selected group of compounds was identified in silico and further evaluated in cell-based assays for cytotoxicity and 11β-HSD1 mediated cortisol production inhibitory capacity. The expression of 11β-HSD1 and 11β-HSD2 in human LS14 adipocytes was assessed during differentiation. Biological evaluation of 39 compounds in adipocytes and steroids quantification by HPLC-MS/MS identify 4 compounds that exhibit 11β-HSD1 mediated cortisol production inhibitory activity with potencies in the micromolar range. Two compounds showed to be selective for the 11β-HSD1 reductase activity and over 11β-HSD2 isoform, and thus represent novel leads for the development of more active derivatives with higher efficacies targeting intracellular cortisol levels in type 2 diabetes and metabolic syndrome.
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Affiliation(s)
- Carlos F Lagos
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Andrea Vecchiola
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Fidel Allende
- Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Cristobal A Fuentes
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Juan E Tichauer
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Carolina Valdivia
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Sandra Solari
- Department of Clinical Laboratories, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Carmen Campino
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile; Millennium Institute of Immunology and Immunotherapy, Santiago, Chile
| | - Alejandra Tapia-Castillo
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Rene Baudrand
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile; Millennium Institute of Immunology and Immunotherapy, Santiago, Chile
| | - Pia Villarroel
- Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago, Chile
| | - Mariana Cifuentes
- Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Santiago, Chile
| | - Gareth I Owen
- Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Cristian A Carvajal
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile; Millennium Institute of Immunology and Immunotherapy, Santiago, Chile
| | - Carlos E Fardella
- Molecular Endocrinology Laboratory, Department of Endocrinology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile; Millennium Institute of Immunology and Immunotherapy, Santiago, Chile.
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Chapman K, Holmes M, Seckl J. 11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev 2013; 93:1139-206. [PMID: 23899562 DOI: 10.1152/physrev.00020.2012] [Citation(s) in RCA: 603] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Glucocorticoid action on target tissues is determined by the density of "nuclear" receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental "programming." The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.
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Affiliation(s)
- Karen Chapman
- Endocrinology Unit, Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
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McCorvie TJ, Timson DJ. In silico prediction of the effects of mutations in the human UDP-galactose 4'-epimerase gene: towards a predictive framework for type III galactosemia. Gene 2013; 524:95-104. [PMID: 23644136 DOI: 10.1016/j.gene.2013.04.061] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 03/30/2013] [Accepted: 04/11/2013] [Indexed: 10/26/2022]
Abstract
The enzyme UDP-galactose 4'-epimerase (GALE) catalyses the reversible epimerisation of both UDP-galactose and UDP-N-acetyl-galactosamine. Deficiency of the human enzyme (hGALE) is associated with type III galactosemia. The majority of known mutations in hGALE are missense and private thus making clinical guidance difficult. In this study a bioinformatics approach was employed to analyse the structural effects due to each mutation using both the UDP-glucose and UDP-N-acetylglucosamine bound structures of the wild-type protein. Changes to the enzyme's overall stability, substrate/cofactor binding and propensity to aggregate were also predicted. These predictions were found to be in good agreement with previous in vitro and in vivo studies when data was available and allowed for the differentiation of those mutants that severely impair the enzyme's activity against UDP-galactose. Next this combination of techniques were applied to another twenty-six reported variants from the NCBI dbSNP database that have yet to be studied to predict their effects. This identified p.I14T, p.R184H and p.G302R as likely severely impairing mutations. Although severely impaired mutants were predicted to decrease the protein's stability, overall predicted stability changes only weakly correlated with residual activity against UDP-galactose. This suggests other protein functions such as changes in cofactor and substrate binding may also contribute to the mechanism of impairment. Finally this investigation shows that this combination of different in silico approaches is useful in predicting the effects of mutations and that it could be the basis of an initial prediction of likely clinical severity when new hGALE mutants are discovered.
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Affiliation(s)
- Thomas J McCorvie
- School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK
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