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A number sign (#) is used with this entry because the phenotype has been shown to be caused by mutation in the glucokinase gene (GCK; 138079), which maps to chromosome 7.
単一遺伝子による常染色体優性遺伝する若年発症型のインスリン非依存性糖尿病の一つである。
MODY is a form of NIDDM (125853) characterized by monogenic autosomal dominant transmission and early age of onset. For a phenotypic description and 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 this 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). Direct relationship was proved by the demonstration of a point mutation in the GCK gene in one of the French families (Vionnet et al., 1992); see 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.
Animal Model
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 had been found previously in human MODY2 patients, and 1 was found previously in a patient with permanent neonatal diabetes mellitus (PNDM; 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.
MODY
常染色体優性遺伝で若年発症する 2 型糖尿病
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
