Alternative titles; symbols
SNOMEDCT: 237604008; ORPHA: 552; DO: 0111100;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p13 | MODY, type II | 125851 | Autosomal dominant | 3 | GCK | 138079 |
A number sign (#) is used with this entry because maturity-onset diabetes of the young type 2 (MODY2) is caused by heterozygous mutation in the GCK gene (138079) on chromosome 7p13.
MODY is a form of NIDDM (125853) characterized by monogenic autosomal dominant transmission and early age of onset. For a general phenotypic description and a discussion of genetic heterogeneity of MODY, see 606391.
In a review of the various forms of MODY, Fajans et al. (2001) stated that glucokinase-related MODY2 is a common form of the disorder, especially in children with mild hyperglycemia and in women with gestational diabetes and a family history of diabetes. It has been described in persons of all racial and ethnic groups. More than 130 MODY-associated mutations have been found in the glucokinase gene. Heterozygous mutations in glucokinase are associated with a mild form of nonprogressive hyperglycemia that is usually asymptomatic at diagnosis and is treated with diet alone. The mild fasting hyperglycemia with blood glucose concentrations of 110 to 145 mg/deciliter and impaired glucose tolerance in most affected carriers may be recognized by biochemical testing at a young age, possibly as early as birth. About 50% of the women who are carriers may have gestational diabetes. Less than 50% of the carriers have overt diabetes; many of those who do are obese or elderly. Two percent of MODY2 patients require insulin therapy. Diabetes-associated complications are rare in this form of MODY. MODY was found in 13% of the Caucasian NIDDM families collected in France by Froguel et al. (1991). Gidh-Jain et al. (1993) found that GCK mutations accounted for 56% of MODY families in France.
Froguel et al. (1992) reported linkage between MODY in 16 French families and the GCK locus on chromosome 7. There was statistically significant evidence of genetic heterogeneity, with an estimated 45 to 95% of the 16 families showing linkage to glucokinase. In those families with linkage to GCK, the possibility of direct etiologic relationship to variation at the GCK locus was raised by Froguel et al. (1992).
In affected members of a French family with MODY mapping to chromosome 7, previously studied by Froguel et al. (1992), Vionnet et al. (1992) identified a point mutation in the GCK gene (138079.0001).
Hattersley et al. (1998) found that mutations in the GCK gene result in reduced birth weight as well as causing MODY.
Barrio et al. (2002) estimated the prevalence of major MODY subtypes in Spanish MODY families and analyzed genotype-phenotype correlations. Twenty-two unrelated pediatric MODY patients and 97 relatives were screened for mutations in the coding region of the GCK, HNF1A (142410), and HNF4A (600281) genes using PCR-SSCP and/or direct sequencing. Mutations in MODY genes were identified in 64% of the families. GCK/MODY2 mutations were the most frequently found, in 41%: 7 novel and 2 theretofore described mutations. The age at diagnosis was prepubertal in MODY2 index patients and pubertal in MODY3 patients. Overt diabetes was rare in MODY2 and was invariably present in MODY3 index patients. Chronic complications of diabetes were absent in the MODY2 population and were present in more than 40% of all relatives of MODY3 patients. Birth weight was lower in the presence of a GCK fetal mutation when the mutation was of paternal origin. The authors concluded that mutations in the GCK/MODY2 gene are the most common cause of MODY in their population of pediatric and adolescent index patients. Clinical expression of MODY3 and MODY1 mutations, the second and third groups of defects found, was more severe, including the frequent development of chronic complications.
Vits et al. (2006) identified 19 different GCK mutations, including 11 novel mutations (see, e.g., 138079.0014), in 33 (26.6%) of 124 Belgian probands with MODY.
Pinterova et al. (2007) screened the GCK gene in 92 Czech probands fulfilling classic MODY criteria and identified 15 different missense mutations in 27 (29%) patients; the mutations were not found in 50 unrelated healthy Czech individuals. Pinterova et al. (2007) concluded that mutations in GCK are a common cause of MODY in the Czech population.
In a mainland Chinese family with a clinical profile similar to that of previously reported MODY2 families, Shen et al. (2011) analyzed the GCK gene and identified a heterozygous missense mutation (E339K; 138079.0016) that segregated with the disease and was not found in 200 controls. The authors noted that MODY2 was rare in Asian families and that mutation in the GCK gene had not previously been reported in MODY patients from the Chinese mainland.
Mirshahi et al. (2022) comprehensively assessed the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for more than 80% of monogenic diabetes. Mirshahi et al. (2022) analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort of 132,194 individuals, and a UK population-based cohort of 198,748 individuals, and found that 1 in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of pathogenic GCK variants was similar (89 to 97%) across all cohorts. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts, highlighting the role of environment/ other genetic factors. The authors suggested that for HNF1A and HNF4A, genetic interpretation and counseling should be tailored to the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings.
Using N-ethyl-N-nitrosourea (ENU) mutagenesis, Inoue et al. (2004) generated diabetic mice. The authors screened 9,375 animals and identified 11 mutations in the glucokinase (Gk) gene that were associated with hyperglycemia. Four of the mutations had previously been found in patients with MODY2, and 1 had been found in a patient with permanent neonatal diabetes mellitus (PNDM1; 606176). Some of the Gk mutant lines displayed impaired glucose-responsive insulin secretion, and the mutations had different effects on Gk mRNA levels and/or the stability of the GK protein.
Barrio, R., Bellanne-Chantelot, C., Moreno, J. C., Morel, V., Calle, H., Alonso, M., Mustieles, C. Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J. Clin. Endocr. Metab. 87: 2532-2539, 2002. [PubMed: 12050210] [Full Text: https://doi.org/10.1210/jcem.87.6.8530]
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://doi.org/10.1056/NEJMra002168]
Froguel, P., Vaxillaire, M., Sun, F., Velho, G., Zouali, H., Butel, M. O., Lesage, S., Vionnet, N., Clement, K., Fougerousse, F., Tanizawa, Y., Weissenbach, J., Beckmann, J. S., Lathrop, G. M., Passa, P., Permutt, M. A., Cohen, D. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356: 162-164, 1992. Note: Erratum: Nature 357: 607 only, 1992. [PubMed: 1545870] [Full Text: https://doi.org/10.1038/356162a0]
Froguel, P., Velho, G., Cohen, D., Passa, P. Strategies for the collection of sibling-pair data for genetic studies in type 2 (non insulin-dependent) diabetes mellitus. (Letter) Diabetologia 34: 685 only, 1991. [PubMed: 1955104] [Full Text: https://doi.org/10.1007/BF00401001]
Gidh-Jain, M., Takeda, J., Xu, L. Z., Lange, A. J., Vionnet, N., Stoffel, M., Froguel, P., Velho, G., Sun, F., Cohen, D., Patel, P., Lo, Y.-M. D., Hattersley, A. T., Luthman, H., Wedell, A., St. Charles, R., Harrison, R. W., Weber, I. T., Bell, G. I., Pilkis, S. J. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc. Nat. Acad. Sci. 90: 1932-1936, 1993. [PubMed: 8446612] [Full Text: https://doi.org/10.1073/pnas.90.5.1932]
Hattersley, A. T., Beards, F., Ballantyne, E., Appleton, M., Harvey, R., Ellard, S. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nature Genet. 19: 268-270, 1998. [PubMed: 9662401] [Full Text: https://doi.org/10.1038/953]
Inoue, M., Sakuraba, Y., Motegi, H., Kubota, N., Toki, H., Matsui, J., Toyoda, Y., Miwa, I., Terauchi, Y., Kadowaki, T., Shigeyama, Y., Kasuga, M. A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program. Hum. Molec. Genet. 13: 1147-1157, 2004. [PubMed: 15102714] [Full Text: https://doi.org/10.1093/hmg/ddh133]
Mirshahi, U. L., Colclough, K., Wright, C. F., Wood, A. R., Beaumont, R. N., Tyrrell, J., Laver, T. W., Stahl, R., Golden, A., Goehringer, J. M, Geisinger-Regeneron DiscovEHR Collaboration, Frayling, T. F., Hattersley, A. T., Carey, D. J., Weedon, M. N., Patel, K. A. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am. J. Hum. Genet. 109: 2018-2028, 2022. [PubMed: 36257325] [Full Text: https://doi.org/10.1016/j.ajhg.2022.09.014]
Pinterova, D., Ek, J., Kolostova, K., Pruhova, S., Novota, P., Romzova, M., Feigerlova, E., Cerna, M., Lebl, J., Pedersen, O., Hansen, T. Six novel mutations in the GCK gene in MODY patients. (Letter) Clin. Genet. 71: 95-96, 2007. [PubMed: 17204055] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00729.x]
Shen, Y., Cai, M., Liang, H., Wang, H., Weng, J. Insight into the biochemical characteristics of a novel glucokinase gene mutation. Hum. Genet. 129: 231-238, 2011. [PubMed: 21104275] [Full Text: https://doi.org/10.1007/s00439-010-0914-4]
Vionnet, N., Stoffel, M., Takeda, J., Yasuda, K., Bell, G. I., Zouali, H., Lesage, S., Velho, G., Iris, F., Passa, P., Froguel, P., Cohen, D. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 356: 721-722, 1992. [PubMed: 1570017] [Full Text: https://doi.org/10.1038/356721a0]
Vits, L., Beckers, D., Craen, M., de Beaufort, C., Vanfleteren, E., Dahan, K., Nollet, A., Vanhaverbeke, G., Imschoot, S. V., Bourguignon, J.-P., Beauloye, V., Storm, K., Massa, G., Giri, M., Nobels, F., De Schepper, J., Rooman, R., Van den Bruel, A., Mathieu, C., Wuyts, W. Identification of novel and recurrent glucokinase mutations in Belgian and Luxembourg maturity onset diabetes of the young patients. (Letter) Clin. Genet. 70: 355-359, 2006. [PubMed: 16965331] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00686.x]