Functional Analyses of HNF1A-MODY Variants Refine the Interpretation of Identified Sequence Variants
| العنوان: | Functional Analyses of HNF1A-MODY Variants Refine the Interpretation of Identified Sequence Variants |
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| المؤلفون: | Jana Malikova, Pavla Dvorakova Kankova, Janniche Torsvik, Petra Dusatkova, Stepanka Pruhova, Klara Vesela, Alba Kaci, Ingvild Aukrust, Lise Bjørkhaug, Pål R. Njølstad |
| المصدر: | e1377-e1386 Journal of Clinical Endocrinology and Metabolism |
| بيانات النشر: | The Endocrine Society, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, medicine.medical_specialty, reclassification, Endocrinology, Diabetes and Metabolism, In silico, Clinical Biochemistry, 030209 endocrinology & metabolism, Context (language use), Type 2 diabetes, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, HNF1A-MODY, medicine, Humans, Hepatocyte Nuclear Factor 1-alpha, Family history, Gene, Genetics, Biochemistry (medical), Prognosis, functional study, medicine.disease, Phenotype, hepatocyte nuclear factor-1 alpha variants, 3. Good health, HNF1A, Diabetes Mellitus, Type 1, 030104 developmental biology, Diabetes Mellitus, Type 2, ACMG classification, Mutation, Medical genetics, Female, Biomarkers, Follow-Up Studies |
| الوصف: | Context While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic. Objective We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry. Design, Settings, and Participants We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization). Results Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Phe215SerfsTer18, p.Gly253Arg, p.Leu383ArgfsTer3, p.Gly437Val, and p.Thr563HisfsTer85) exhibited significantly reduced transcriptional activity or DNA binding (< 40%) and were classified as (likely) pathogenic, 2/17 variants were (likely) benign and 3/17 remained of uncertain significance. Functional analyses allowed for the reclassification of 10/17 variants (59%). Diabetes treatment was improved in 20/29 (69%) carriers of (likely) pathogenic HNF1A variants. Conclusion Functional evaluation of the HNF1A variants is necessary to better predict the pathogenic effects and to improve the diagnostic interpretation and treatment, particularly in cases where the cosegregation or family history data are not available or where the phenotype is more diverse and overlaps with other types of diabetes. |
| وصف الملف: | application/pdf |
| تدمد: | 1945-7197 0021-972X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5c2e18edabd2e6536fcbaa65942cba5eTest https://doi.org/10.1210/clinem/dgaa051Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5c2e18edabd2e6536fcbaa65942cba5e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19457197 0021972X |
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