Alternative titles; symbols
SNOMEDCT: 609561005; ORPHA: 552; DO: 0050524;
A number sign (#) is used with this entry because maturity-onset diabetes of the young (MODY) can be caused by mutation in several different genes.
Maturity-onset diabetes of the young is an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but represents genetic, metabolic, and clinical heterogeneity (Vaxillaire and Froguel, 2008).
Genetic Heterogeneity of MODY
MODY1 (125850) is caused by heterozygous mutation in the hepatocyte nuclear factor-4-alpha gene (HNF4A; 600281) on chromosome 20.
MODY2 (125851) is caused by heterozygous mutation in the glucokinase gene (GCK; 138079) on chromosome 7.
MODY3 (600496) is caused by heterozygous mutation in the hepatocyte nuclear factor-1alpha gene (HNF1A; 142410) on chromosome 12q24.2.
MODY4 (606392) is caused by heterozygous mutation in the pancreas/duodenum homeobox protein-1 gene (PDX1; 600733) on chromosome 13q12.1.
MODY5 (137920) is caused by heterozygous mutation in the gene encoding hepatic transcription factor-2 (TCF2; 189907) on chromosome 17cen-q21.3.
MODY6 (606394) is caused by heterozygous mutation in the NEUROD1 gene (601724) on chromosome 2q32.
MODY7 (610508) is caused by heterozygous mutation in the KLF11 gene (603301) on chromosome 2p25.
MODY8 (609812), or diabetes-pancreatic exocrine dysfunction syndrome, is caused by heterozygous mutation in the CEL gene (114840) on chromosome 9q34.
MODY9 (612225) is caused by heterozygous mutation in the PAX4 gene (167413) on chromosome 7q32.
MODY10 (613370) is caused by heterozygous mutation in the insulin gene (INS; 176730) on chromosome 11p15.5.
MODY11 (613375) is caused by heterozygous mutation in the BLK gene (191305) on chromosome 8p23.
MODY13 (616329) is caused by heterozygous mutation in the KCNJ11 gene (600937) on chromosome 11p15.
MODY14 (616511) is caused by heterozygous mutation in the APPL1 gene (604299) on chromosome 3p14.
The term 'maturity-onset diabetes of the young,' or MODY, relies on the old classification of diabetes into juvenile-onset and maturity-onset diabetes. A revised, etiology-based classification for diabetes was introduced by both the American Diabetes Association and the World Health Organization, and MODY is now included in the group of 'genetic defect in beta-cell function' with a subclassification according to the gene involved (Vaxillaire and Froguel, 2008).
Glaser (2003) stated that although MODY is typically used to indicate autosomal dominant noninsulin-dependent diabetes diagnosed before the age of 25 years, there is an increasing incidence of polygenic type 2 diabetes (125853) in childhood and adolescence, and patients with gene mutations characteristic of MODY often present with clinical diabetes later in life. He therefore suggested abandoning the term MODY and substituting the term autosomal dominant type 2 diabetes, just as the terms maturity-onset diabetes and noninsulin-dependent diabetes have been abandoned for describing polygenic type 2 diabetes. He cited the case described by Huopio et al. (2003) with a dominant mutation in the sulfonylurea receptor-1 gene (ABCC8; 600509.0011) that caused congenital hyperinsulinism in infancy, loss of insulin secretory capacity in early adulthood, and diabetes mellitus in middle age. Huopio et al. (2003) noted that, except for age at presentation, the mutation in the ABCC8 gene causes a disorder that fulfills the criteria for a form of MODY. They suggested that the ABCC8 gene qualified as the seventh gene associated with autosomal dominant type 2 diabetes.
Tattersall (1974) described 3 families with an autosomal dominant form of diabetes. This form had early onset, but mild and relatively uncomplicated course. For example, 7 out of 12 diabetics diagnosed under the age of 30 years had no retinopathy after an average duration of 37 years. In 2 of the families diabetes was associated with a low renal threshold for glucose. They noted transmission over at least 3 generations with 50% of affected children of an affected parent, and an affected parent of almost all affected persons. Further evidence for a separate autosomal dominant form was provided by Tattersall and Fajans (1975) and by Johansen and Gregersen (1977). Nelson and Pyke (1976) referred to this as maturity-onset diabetes of the young. It has also been called the Mason type, after the family in which it was first observed. Despite the early onset, the natural history is that of the late-onset type.
Irvine et al. (1977) concluded from a family study that insulin dependence or independence is a better means of separating distinct forms of diabetes mellitus than is age of onset.
See 118430 for a discussion of chlorpropamide-alcohol flushing, which may be a marker for this form of diabetes.
Vaxillaire and Froguel (2008) noted that 5 major diagnostic criteria for MODY are usually accepted: (1) hyperglycemia usually diagnosed before age 25 years in at least 1 and ideally 2 family members; (2) autosomal dominant inheritance, with a vertical transmission of diabetes through at least 3 generations, and a similar phenotype shared by diabetic family members; (3) absence of insulin therapy at least 5 years after diagnosis or significant C-peptide levels even in a patient on insulin treatment; (4) insulin levels that are often in the normal range, although inappropriately low for the degree of hyperglycemia, suggesting a primary defect in beta-cell function; and (5) overweight or obesity is rarely associated (and is not required for the development of diabetes).
Rimoin (1979) stated that MODY has an unusually high prevalence in Romania.
Winter et al. (1987) found that MODY is unusually frequent in black Americans. This atypical form was found in 12 of 129 black patients with youth-onset diabetes and in at least 2 generations in 9 of the 12 families of the probands. Fourteen of the diabetic relatives as well as the 12 probands were studied. Islet cell autoantibodies were not found in any, and thyroid microsomal autoantibodies were found in only one. The frequencies of the insulin-dependent-diabetes-associated antigens HLA-DR3 and -DR4 were not increased among the probands, and diabetes did not cosegregate with HLA haplotypes in the informative families.
Ledermann (1995) stated that the prevalence of MODY is about 5% of type 2 diabetes patients in most populations.
Fajans et al. (2001) stated that families whose members have a clinical history compatible with the diagnosis of MODY but who do not have mutations in any of the 6 known MODY-related genes account for an estimated 15 to 20% of Europeans with clinical MODY and as many as 80% of Japanese persons with clinical MODY.
MODY3 and MODY2 are the 2 most prevalent forms of MODY, accounting for more than 80% of MODY patients in Caucasians (Frayling et al., 2001). Mutations in the HNF4A gene are less common and are found in 1 of 57 Japanese patients with MODY (Furuta et al., 1997). Other subtypes are rare disorders reported in only a few families. Yamada et al. (2000) suggested that about 80% of Japanese MODY patients cannot be explained by known MODY genes.
Xu et al. (2005) studied 146 Chinese families fulfilling the minimum criteria for MODY: 2 consecutive generations of type 2 diabetes with at least 1 member diagnosed under the age of 25 years. Thirteen families had MODY3 mutations and 2 had MODY2 mutations. No MODY1 mutation was found. Four of the 12 different MODY3 mutations were novel. The authors referred to the untyped cases as MODYX. MODY3 and MODY2 accounted for only 9 and 1%, respectively, of Chinese MODY. Xu et al. (2005) concluded that the majority of Chinese MODY patients are due to defects in unknown genes and appear to be characterized by insulin resistance.
Kayashima et al. (2002) described a 20-year-old man with maternal uniparental disomy for chromosome 14 and maturity-onset diabetes mellitus. He had pre- and postnatal growth retardation, developed diabetes mellitus at age 20 years without any autoimmune antibodies, and had a mosaic karyotype interpreted as representing segmental maternal isodisomy for 14q21-q24 and maternal heterodisomy of the remaining regions of the chromosome. Kayashima et al. (2002) speculated that the segmental isodisomy led to reduction to homozygosity for a mutant gene and thus caused the patient's diabetes mellitus. FISH analysis using BAC clones revealed that the isodisomic segment did not overlap any known IDDM or NIDDM susceptibility loci on chromosome 14, suggesting a novel locus for a subset of diabetes mellitus located at the isodisomic segment.
Johnston et al. (1984) could demonstrate no linkage (or association) with a particular polymorphism of the sequences flanking the insulin gene, and Bell et al. (1983) found no linkage to the insulin gene. In 3 families with MODY and 7 with 'common' type II diabetes mellitus, O'Rahilly et al. (1992) excluded linkage to the INS locus.
Bell, J. I., Wainscoat, J. S., Old, J. M., Chlouverakis, C., Keen, H., Turner, R. C., Weatherall, D. J. Maturity onset diabetes of the young is not linked to the insulin gene. Brit. Med. J. 286: 590-593, 1983. [PubMed: 6402160] [Full Text: https://dx.doi.org/10.1136/bmj.286.6365.590]
Fajans, S. S., Bell, G. I., Polonsky, K. S. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. New Eng. J. Med. 345: 971-980, 2001. [PubMed: 11575290] [Full Text: https://dx.doi.org/10.1056/NEJMra002168]
Frayling, T. M., Evans, J. C., Bulman, M. P., Pearson, E., Allen, L., Owen, K., Bingham, C., Hannemann, M., Shepherd, M., Ellard, S., Hattersley, A. T. Molecular and clinical characterization of mutations in transcription factors. Diabetes 50 (Suppl. 1): S94-S100, 2001. [PubMed: 11272211] [Full Text: https://dx.doi.org/10.2337/diabetes.50.2007.s94]
Furuta, H., Iwasaki, N., Oda, N., Hinokio, Y., Horikawa, Y., Yamagata, K., Yano, N., Sugahiro, J., Ogata, M., Ohgawara, H., Omori, Y., Iwamoto, Y., Bell, G. I. Organization and partial sequence of the hepatocyte nuclear factor-4-alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes 46: 1652-1657, 1997. [PubMed: 9313765] [Full Text: https://dx.doi.org/10.2337/diacare.46.10.1652]
Glaser, B. Dominant SUR1 mutation causing autosomal dominant type 2 diabetes. (Commentary) Lancet 361: 272-273, 2003. [PubMed: 12559857] [Full Text: https://dx.doi.org/10.1016/S0140-6736(03)12363-X]
Haneda, M., Chan, S. J., Kwok, S. C. M., Rubenstein, A. H., Steiner, D. F. Studies on mutant human insulin genes: identification and sequence analysis of a gene encoding (Ser-B24) insulin. Proc. Nat. Acad. Sci. 80: 6366-6370, 1983. [PubMed: 6312455] [Full Text: https://dx.doi.org/10.1073/pnas.80.20.6366]
Huopio, H., Otonkoski, T., Vauhkonen, I., Reimann, F., Ashcroft, F. M., Laakso, M. A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet 361: 301-307, 2003. [PubMed: 12559865] [Full Text: https://dx.doi.org/10.1016/S0140-6736(03)12325-2]
Irvine, W. J., Holton, D. E., Clarke, B. F., Toft, A. D., Prescott, R. J., Duncan, L. J. P. Familial studies of type-I and type-II idiopathic diabetes mellitus. Lancet 310: 325-328, 1977. Note: Originally Volume II. [PubMed: 69935] [Full Text: https://dx.doi.org/10.1016/s0140-6736(77)91486-6]
Johansen, K., Gregersen, G. A family with dominantly inherited mild juvenile diabetes. Acta Med. Scand. 201: 567-570, 1977. [PubMed: 878915] [Full Text: https://dx.doi.org/10.1111/j.0954-6820.1977.tb15749.x]
Johnston, C., Owerbach, D., Leslie, R. D. G., Pyke, D. A., Nerup, J. Mason-type diabetes and DNA insertion polymorphism. (Letter) Lancet 323: 280 only, 1984. Note: Originally Volume I. [PubMed: 6143020] [Full Text: https://dx.doi.org/10.1016/s0140-6736(84)90153-3]
Kayashima, T., Katahira, M., Harada, N., Miwa, N., Ohta, T., Yoshiura, K., Matsumoto, N., Nakane, Y., Nakamura, Y., Kajii, T., Niikawa, N., Kishino, T. Maternal isodisomy for 14q21-q24 in a man with diabetes mellitus. Am. J. Med. Genet. 111: 38-42, 2002. [PubMed: 12124731] [Full Text: https://dx.doi.org/10.1002/ajmg.10511]
Ledermann, H. M. Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed? (Letter) Lancet 345: 648 only, 1995. [PubMed: 7898196] [Full Text: https://dx.doi.org/10.1016/s0140-6736(95)90548-0]
Nelson, P. G., Pyke, D. A. Genetic diabetes not linked to the HLA locus. Brit. Med. J. 1: 196-197, 1976. [PubMed: 1247771] [Full Text: https://dx.doi.org/10.1136/bmj.1.6003.196]
O'Rahilly, S., Patel, P., Lehmann, O. J., Tybjaerg-Hansen, A., Nerup, J., Turner, R. C., Wainscoat, J. S. Multipoint linkage analysis of the short arm of chromosome 11 in non-insulin dependent diabetes including maturity onset diabetes of youth. Hum. Genet. 89: 207-212, 1992. [PubMed: 1587533] [Full Text: https://dx.doi.org/10.1007/BF00217125]
Rimoin, D. L. Personal Communication. Torrance, Calif. 1979.
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Vaxillaire, M., Froguel, P. Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr. Rev. 29: 254-264, 2008. [PubMed: 18436708] [Full Text: https://dx.doi.org/10.1210/er.2007-0024]
Winter, W. E., Maclaren, N. K., Riley, W. J., Clarke, D. W., Kappy, M. S., Spillar, R. P. Maturity-onset diabetes of youth in black Americans. New Eng. J. Med. 316: 285-291, 1987. [PubMed: 3543673] [Full Text: https://dx.doi.org/10.1056/NEJM198702053160601]
Xu, J. Y., Dan, Q. H., Chan, V., Wat, N. M. S., Tam, S., Tiu, S. C., Lee, K. F., Siu, S. C., Tsang, M. W., Fung, L. M., Chan, K. W., Lam, K. S. L. Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. Europ. J. Hum. Genet. 13: 422-427, 2005. [PubMed: 15657605] [Full Text: https://dx.doi.org/10.1038/sj.ejhg.5201347]
Yamada, S., Zhu, Q., Aihara, Y., Onda, H., Zhang, Z., Yu, L., Jin, L., Si, Y.-J., Nishigori, H., Tomura, H., Inoue, I., Morikawa, A., Yamagata, K., Hanafusa, T., Matsuzawa, Y., Takeda, J. Cloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3-beta and mutation screening in Japanese subjects with maturity-onset diabetes of the young. Diabetologia 43: 121-124, 2000. [PubMed: 10672453] [Full Text: https://dx.doi.org/10.1007/s001250050016]