beta-cell genes and diabetes - Molecular and clinical characterization of mutations in transcription factors

beta -Cell transcription factor genes are important in the pathophysiology of the beta -cell, with mutations in hepatocyte nuclear factor (HNF)-1 alph a, HNF-4 alpha, insulin promoter factor (IPF)-1, HNF-1 beta, and NeuroD1/BE TA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage a nd sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). Th e relative distribution of the 90 families fitting maturity-onset diabetes of the young (MODY) criteria was 63% HNF-1 alpha, 2% HNF-4 alpha, 0% IPF-1, 1% HNF-1 beta, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molec ular genetic and clinical characteristics of these patients including 29 ne w families and 8 novel HNF-1 alpha gene mutations. Mutations in the transac tivation domain are more likely to be protein truncating rather than result in amino acid substitutions, suggesting that a relatively severe disruptio n of this domain is necessary to result in diabetes. Mutations in the diffe rent transcription factors result in clinical heterogeneity. IPF-1 mutation s are associated with a higher age at diagnosis (42.7 years) than HNF-1 alp ha (20.4 years), HNF-1 beta (24.2 years), or HNF-4 alpha (26.3 years) gene mutations. Subjects with HNF-1 beta mutations, in contrast to the other tra nscription factors, frequently present with renal disease. A comparison of age at diagnosis between subjects with different types and locations of HNF -1 alpha mutations did not reveal genotype-phenotype correlations. In concl usion, mutations in transcription factors expressed in the beta -cellw are the major cause of MODY, and the phenotype clearly varies with the gene tha t is mutated. There is little evidence to indicate that different mutations within the same gene have different phenotypes.