Genotype-based personalized correction of glycemic control in patients with MODY due to mutations in GCK, HNF1A AND HNF4A genes

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Abstract


Aims. To demonstrate the principles of personalized treatment of diabetes for example the most common MODY subtypes (1-3) identified by NGS

Methods. We study 312 patients aged from 3 months to 25 years (162 boy/150 girls) with suspected MODY. A targeted next-generation sequencing approach (IonTorrent platform) was used for sequencing of monogenic form of diabetes mellitus candidate 28genes (13 MODY genes-candidates and other genes, associated with diabetes mellitus). Clinical and biochemicalphenotypes of the patients were compared with the type of mutations. Previously undescribed nonsynonymous mutations were considered as «probably pathogenic» with the minor allele frequency of <0.1% and «pathogenic» assessment in ANNOVAR database.

Results. We selected group of patients with mutations in the most common genes-candidates (GCK; HNF1A; HNF4A):99GCK gene mutations detectedin the 129 probands (61,1%) and 77 relatives, in HNF1A – 20 mutations in the 19 probands(9,0%) and 14 relatives, in HNF4A – 8 mutations in 9the probands (4,3%) and 3 relatives. The current therapy wasmodificated account the genotype and have been evaluated its effectiveness.

Conclusion. Molecular genetic confirmation of the monogenic nature of metabolic carbohydratedisorders is the basis of personalized therapy of diabetes.


Natalia A. Zubkova

Endocrinology research centre

Author for correspondence.
Email: zunata2006@yandex.ru
ORCID iD: 0000-0002-1346-7545
SPIN-code: 5064-9992

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

MD, PhD

Olesya A. Gioeva

Endocrinology research centre

Email: olesyasogma@mail.ru
ORCID iD: 0000-0001-9189-4596
SPIN-code: 4994-4126

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

MD

Yulia V. Tikhonovich

Endocrinology research centre

Email: yuliatihonovich@mail.ru
ORCID iD: 0000-0001-7747-6873
SPIN-code: 6492-6790

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

MD, PhD

Vasily M. Petrov

Endocrinology research centre

Email: petrov.vasiliy@gmail.com
ORCID iD: 0000-0002-0520-9132
SPIN-code: 4358-2147

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

PhD

Evgeny V. Vasiliev

Endocrinology research centre

Email: vas-evg@yandex.ru
ORCID iD: 0000-0003-1107-362X
SPIN-code: 5767-1569

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

PhD

Anatoliy N. Tyulpakov

Endocrinology research centre

Email: ant@endocrincentr.ru
ORCID iD: 0000-0001-8500-4841
SPIN-code: 8396-1798

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

MD, PhD

Ivan I. Dedov

Endocrinology research centre

Email: dedov@endocrincentr.ru
ORCID iD: 0000-0002-8175-7886
SPIN-code: 5873-2280

Russian Federation, 11, Dm. Ulyanova street, Moscow, 117036

MD, PhD, Professor

  1. Baltimore D. Our genome unveiled. Nature. 2001;409(6822):814-816. doi: 10.1038/35057267.
  2. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860-921. doi: 10.1038/35057062.
  3. Peltonen L, McKusick VA. Genomics and medicine. Dissecting human disease in the postgenomic era. Science. 2001;291(5507):1224-1229. doi: 10.1126/science.291.5507.1224.
  4. Tuomi T, Santoro N, Caprio S, et al. The many faces of diabetes: a disease with increasing heterogeneity. Lancet. 2014;383(9922):1084-1094. doi: 10.1016/S0140-6736(13)62219-9.
  5. Дедов И.И., Шестакова М.В. Персонализированная терапия сахарного диабета: путь от болезни к больному. // Терапевтический архив. – 2014. – Т. 86. – №10. – С. 4-9. [Dedov II, Shestakova MV. Personalized therapy for diabetes mellitus: the path from disease to the patient. TerArkh. 2014;86(10):4-9. (in Russ.)]
  6. Tattersall RB. Mild familial diabetes with dominant inheritance. Q J Med. 1974;43(170):339-357. PMID:4212169.
  7. Tattersall RB, Fajans SS, Arbor A. A Difference Between the Inheritance of Classical Juvenile-onset and Maturity-onset Type Diabetes of Young People. Diabetes. 1975;24(1):44-53. doi: 10.2337/diab.24.1.44.
  8. Froguel P, Vaxillaire M, Sun F, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature. 1992;356(6365):162-164. doi: 10.1038/356162a0.
  9. Froguel P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med. 1993;328(10):697-702. doi: 10.1056/NEJM199303113281005.
  10. Schnyder S, Mullis PE, Ellard S, et al. Genetic testing for glucokinase mutations in clinically selected patients with MODY: a worthwhile investment. Swiss Med Wkly. 2005;135(23-24):352-356. doi: 2005/23/smw-11030.
  11. Lin HV, Accili D. Hormonal regulation of hepatic glucose production in health and disease. CellMetab. 2011;14(1):9-19. doi: 10.1016/j.cmet.2011.06.003.
  12. Gill-Carey O, Shields B, Colclough K, et al. Finding a glucokinase mutation alters patient treatment. DiabetMed. 2007;24(Suppl 1):6.
  13. Shih DQ, Stoffel M. Dissecting the transcriptional network of pancreatic islets during development and differentiation. Proc Natl AcadSci U S A. 2001;98(25):14189-14191. doi: 10.1073/pnas.251558998.
  14. Stoffel M, Le Beau MM, Espinosa R, 3rd, et al. A yeast artificial chromosome-based map of the region of chromosome 20 containing the diabetes-susceptibility gene, MODY1, and a myeloid leukemia related gene. Proc Natl AcadSci U S A. 1996;93(9):3937-3941. PMC39463.
  15. Vaxillaire M, Boccio V, Philippi A, et al. A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nat Genet. 1995;9(4):418-423. doi: 10.1038/ng0495-418.
  16. Pontoglio M, Barra J, Hadchouel M, et al. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell. 1996;84(4):575-585. doi: 10.1016/S0092-8674(00)81033-8.
  17. Colclough K, Bellanne-Chantelot C, Saint-Martin C, et al. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat. 2013;34(5):669-685. doi: 10.1002/humu.22279.
  18. Pontoglio M, Prie D, Cheret C, et al. HNF1alpha controls renal glucose reabsorption in mouse and man. EMBO Rep. 2000;1(4):359-365. doi: 10.1093/embo-reports/kvd071.
  19. 19.Pearson ER, Boj SF, Steele AM, et al. Macrosomia and hyperinsulinaemichypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118. doi: 10.1371/journal.pmed.0040118.
  20. Ryffel GU. Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences. J MolEndocrinol. 2001;27(1):11-29. doi: 10.1677/jme.0.0270011.
  21. Isomaa B, Henricsson M, Lehto M, et al. Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia. 1998;41(4):467-473. doi: 10.1007/s001250050931.

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Copyright (c) 2017 Zubkova N.A., Gioeva O.A., Tikhonovich Y.V., Petrov V.M., Vasiliev E.V., Tyulpakov A.N., Dedov I.I.

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