Review
Molecular Genetics of Maturity-onset Diabetes of the Young

https://doi.org/10.1016/S1043-2760(98)00134-9Get rights and content

Abstract

Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of Type 2 diabetes characterized by early onset, autosomal dominant inheritance and primary defects in insulin secretion. To date, five proteins have been identified whose genetic absence or impairment causes MODY, the enzyme glucokinase (GCK/MODY2) and four transcription factors: hepatocyte nuclear factor 4α (HNF-4α/MODY1), HNF-1α/MODY3, insulin promoter factor 1 (IPF-1/MODY4) and HNF-1β/MODY5. Additional MODY genes remain to be identified.

Section snippets

Glucokinase Mutations and MODY2

Glucokinase (GCK) phosphorylates glucose to glucose-6-phosphate in pancreatic β cells and hepatocytes, and plays a major role in the regulation and integration of glucose metabolism16. More than 80 different GCK mutations have been found to date6, 17. Expression studies have shown that the enzymatic activity of the mutant proteins is impaired, with either a decrease of Vmax and/or a decrease of the affinity of the enzyme for glucose18. Impairment in the enzymatic activity of mutant GCK results

Mutations in Transcription Factor Genes

Positional cloning of MODY genes has led to the identification of mutations in four transcription factors: HNF-1α, HNF-1β, HNF-4α and IPF-1 (3, 8, 11, 12). The HNFs are nuclear proteins, initially found to be expressed in the liver. They were well known to modulate the expression of many hepatic genes, such as albumin and Apo C3 (Ref. 24), but their role in pancreatic islets and in the kidney was unknown until recently (Fig. 1). For a long time they have not been considered as obvious

Conclusions

The identification of GCK as a diabetes susceptibility gene has provided a major impulse for the reassessment of its physiological role as a ‘glucose sensor’ and the understanding of the patho-physiological importance of this key enzyme of glucose homeostasis. More recently, the recognition of the role of transcription factors in MODY has opened new perspectives in the understanding and treatment of Type 2 diabetes and of the mechanisms of glucose homeostasis. Only a small proportion of

References (48)

  • K. Yamagata

    Mutations in the hepatocyte nuclear factor 1 alpha gene in maturity-onset diabetes of the young (MODY3)

    Nature

    (1996)
  • M. Vaxillaire

    Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3)

    Hum. Mol. Genet.

    (1997)
  • D.A. Stoffers et al.

    Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence

    Nat. Genet.

    (1997)
  • D.A. Stoffers et al.

    Early-onset type 2 diabetes mellitus (MODY4) linked to IPF1

    Nat. Genet.

    (1997)
  • Y. Horikawa

    Mutation in hepatocyte nuclear factor-1β gene (TCF2) associated with MODY

    Nat. Genet.

    (1997)
  • J.C. Chèvre

    Mutation screening in 18 Caucasian families suggests the existence of other MODY genes

    Diabetologia

    (1998)
  • T.M. Frayling

    Mutations in the hepatocyte nuclear factor-1 alpha gene are a common cause of maturity-onset diabetes of the young in the U.K.

    Diabetes

    (1997)
  • F.M. Matschinsky

    A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm

    Diabetes

    (1996)
  • H. Blanché

    Criblage moléculaire de la glucokinase: 37 nouvelles mutations

    Diabetes Metabol.

    (1997)
  • M. Gidh-Jain

    Glucokinase mutations associated with non insulin dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships

    Proc. Natl. Acad. Sci. U. S. A.

    (1993)
  • J. Sturis

    Compensation in pancreatic beta-cell function in subjects with glucokinase mutations

    Diabetes

    (1994)
  • M.M. Byrne

    Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations

    J. Clin. Invest.

    (1994)
  • G. Velho

    Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects

    J. Clin. Invest.

    (1996)
  • G. Velho et al.

    Diabetes complications in NIDDM kindreds linked to the MODY-3 locus on chromosome 12q

    Diabetes Care

    (1996)
  • Cited by (0)

    View full text