Journal List > J Korean Diabetes > v.18(3) > 1055064

TOOLS
Noh: Genetic Diseases Associated with Diabetes Mellitus
Focused Issue

J Korean Diabetes 2017;18(3):169-176.

Published online: 10 January 2017

DOI: https://doi.org/10.4093/jkd.2017.18.3.169

Genetic Diseases Associated with Diabetes Mellitus

Junghyun Noh

Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea

Corresponding author: Junghyun Noh Division of Endocrinology and Metabolism, Department of Internal Medicine, Inje University Ilsan Paik Hospital, 170 Juhwa-ro, Ilsanseo-gu, Goyang 10380, Korea, E-mail: jhnoh@paik.ac.kr

Received 31 July 2017       Accepted 7 August 2017

Copyright © 2016 Korean Diabetes Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Whereas most people with diabetes mellitus have type 1 or type 2 diabetes, there are other inherited forms of diabetes, including single-gene forms of diabetes and rare genetic syndromes. Monogenic forms of pancreatic beta cell dysfunction include maturity-onset diabetes of the young (MODY) and neonatal diabetes, with MODY being the most common form of inherited diabetes. Mitochondrial diabetes and monogenic severe insulin resistance are also inherited forms of diabetes. In addition, more than 100 genetic diseases are known to be associated with diabetes mellitus. Diagnosis of inherited diabetes has important implications for patients, allowing personalized management and screening of their relatives. This review briefly presents genetic diseases associated with diabetes mellitus.

Keywords: Diabetes mellitus, Genetic diseases, inborn, Single-gene diabetes disorder

References

1. Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med. 2001; 345:971–80.
crossref
2. Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue K. International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2006–2007. The diagnosis and management of monogenic diabetes in children. Pediatr Diabetes. 2006; 7:352–60.
crossref
3. Naylor RN, Greeley SA, Bell GI, Philipson LH. Genetics and pathophysiology of neonatal diabetes mellitus. J Diabetes Investig. 2011; 2:158–69.
crossref
4. Colombo C, Delvecchio M, Zecchino C, Faienza MF, Cavallo L, Barbetti F. Early Onset Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetology. Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (KIR6.2) mutation. Diabetologia. 2005; 48:2439–41.
crossref
5. Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006; 355:456–66.
6. Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI. Neonatal Diabetes International Collaborative Group. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A. 2007; 104:15040–4.
7. Njølstad PR, Søvik O, Cuesta-Muñoz A, Bjørkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001; 344:1588–92.
crossref
8. Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med. 2008; 25:383–99.
9. Agarwal AK, Garg A. Genetic disorders of adipose tissue development, differentiation, and death. Annu Rev Genomics Hum Genet. 2006; 7:175–99.
crossref
10. Tritos NA, Mantzoros CS. Clinical review 97: syndromes of severe insulin resistance. J Clin Endocrinol Metab. 1998; 83:3025–30.
11. Iannello S, Bosco P, Cavaleri A, Camuto M, Milazzo P, Belfiore F. A review of the literature of Bardet-Biedl disease and report of three cases associated with metabolic syndrome and diagnosed after the age of fifty. Obes Rev. 2002; 3:123–35.
crossref
12. Antosik K, Borowiec M. Genetic factors of diabetes. Arch Immunol Ther Exp (Warsz). 2016; 64(Suppl 1):157–60.
crossref
13. Milunsky A, Neurath PW. Diabetes mellitus in Down's syndrome. Arch Environ Health. 1968; 17:372–6.
crossref
14. Bergholdt R, Eising S, Nerup J, Pociot F. Increased prevalence of Down's syndrome in individuals with type 1 diabetes in Denmark: a nationwide population-based study. Diabetologia. 2006; 49:1179–82.
crossref
15. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, Bailey R, Nejentsev S, Field SF, Payne F, Lowe CE, Szeszko JS, Hafler JP, Zeitels L, Yang JH, Vella A, Nutland S, Stevens HE, Schuilenburg H, Coleman G, Maisuria M, Meadows W, Smink LJ, Healy B, Burren OS, Lam AA, Ovington NR, Allen J, Adlem E, Leung HT, Wallace C, Howson JM, Guja C, Ionescu-Tîrgovişte C. Genetics of Type 1 Diabetes in Finland. Simmonds MJ, Heward JM, Gough SC. Wellcome Trust Case Control Consortium, Dunger DB, Wicker LS, Clayton DG. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007; 39:857–64.
crossref
16. Lima FA, Moreira-Filho CA, Ramos PL, Brentani H, Lima Lde A, Arrais M, Bento-de-Souza LC, Bento-de-Souza L, Duarte MI, Coutinho A, Carneiro-Sampaio M. Decreased AIRE expression and global thymic hypofunction in Down syndrome. J Immunol. 2011; 187:3422–30.
crossref
17. Bojesen A, Høst C, Gravholt CH. Klinefelter's syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod. 2010; 16:396–401.
crossref
18. Ibarra-Gasparini D, Altieri P, Scarano E, Perri A, Morselli-Labate AM, Pagotto U, Mazzanti L, Pasquali R, Gambineri A. New insights on diabetes in Turner syndrome: results from an observational study in adulthood. Endocrine 2017. doi: 10.1007/s12020-017–1336-z. [Epub ahead of print].
19. Cnop M, Mulder H, Igoillo-Esteve M. Diabetes in Friedreich ataxia. J Neurochem. 2013; 126(Suppl 1):94–102.
crossref
20. Podolsky S, Leopold NA, Sax DS. Increased frequency of diabetes mellitus in patients with Huntington's chorea. Lancet. 1972; 1:1356–8.
crossref
21. Farrer LA. Diabetes mellitus in Huntington disease. Clin Genet. 1985; 27:62–7.
crossref
22. Ørngreen MC, Arlien-Søborg P, Duno M, Hertz JM, Vissing J. Endocrine function in 97 patients with myotonic dystrophy type 1. J Neurol. 2012; 259:912–20.
crossref
23. Lanng S, Thorsteinsson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis. Eur J Pediatr. 1992; 151:684–7.
crossref
24. Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B. CFRD Guidelines Committee. Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care. 2010; 33:2697–708.
crossref
25. Pelusi C, Gasparini DI, Bianchi N, Pasquali R. Endocrine dysfunction in hereditary hemochromatosis. J Endocrinol Invest. 2016; 39:837–47.
crossref

Table 1.
Single-gene diabetes disorders
Type of diabetes Genes Affected protein Age at diabetes presentation
Maturity-onset diabetes of the young (MODY)
MODY 1 HNF4A Hepatocyte nuclear factor 4α Adolescence to early adulthood
MODY 2 GCK Glucokinase Childhood
MODY 3 TCF1 Hepatic nuclear factor 1α Adolescence to early adulthood
MODY 4 IPF1 (PDX1) Insulin promoter factor 1 Early adulthood
MODY 5 TCF2 Hepatic nuclear factor 1β Adolescence to early adulthood
MODY 6 NeuroD1, or BETA2 Neurogenic differentiation factor 1 4th decade of life
Permanent neonatal diabetes mellitus (PNDM)
PNDM KCNJ11 Kir6.2 3∼6 months
PNDM ABCC8 SUR1-sulfonylurea receptor 1 1∼3 months
PNDM GCK Glucokinase 1 week
PNDM IPF1 (PDX1) Insulin promoter factor 1 1 week
PNDM PTF1A Pancreas transcription factor 1 A At birth
PNDM (IPEX syndrome) FOXP3 Forkhead box P3 At birth
PNDM (Wolcott-Rallison syndrome) EIF2AK3 Eukaryotic translation initiation factor 2-alpha kinase 3 3 months
Transient neonatal diabetes mellitus (TNDM)
TNDM ZAC/HYMAI ZAC: pleomorphic adenoma gene-like 1 or PLAG1 HYMAI: hydatiform mole-associated and imprinted transcript Birth to 3 months
TNDM ABCC8 SUR1-sulfonylurea receptor 1 Birth to 6 months
TNDM KCNJ11 Kir6.2 Birth to 6 months
TNDM HNF1 β Hepatocyte nuclear factor 1B Birth to 6 months
Table 2.
Genetic syndromes associated with diabetes mellitus
Name of syndromes Genes Inheritance Age at diabetes presentation
Obesity-related syndromes  
Prader-Willi syndrome Chromosome 15q partial deletion Paternally inherited Childhood to early adulthood
Laurence-Moon syndrome PNPLA6 AR Childhood to early adulthood
Bardet-Biedl syndrome BBS AR Childhood to early adulthood
Alstrom syndrome ALMS1 AR Childhood to early adulthood
Chromosomal disorders
Down syndrome Trisomy of chromosome 21 Sporadic Childhood to early adulthood
Klinefelter syndrome XXY males Sporadic Middle age
Turner syndrome XO females Sporadic, maternal germ cells XO mosaicism Adulthood
Neurodegenerative disorders Friedreich ataxia FXN AR Early adulthood
Huntington's disease HTT gene trinucleotide repeat AD Middle age
Myotonic dystrophy Type 1: DMPK gene trinucleotide repeat Type 2:ZNF9 gene trinucleotide repeat AD Adulthood
Exocrine pancreas disorders Cystic fibrosis CFTR AR Infancy to early adulthood
Hemochromatosis HFE AR Adulthood

AR, autosomal recessive; AD, au utosomal dominant.

TOOLS
Similar articles