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

Abstract

Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulin-dependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4α/MODY1/TCF14) on chromosome 20 q, glucokinase (GCK/MODY2) on chromosome 7p, hepatocyte nuclear factor-1 alpha (HNF-1α/MODY3/TCF1) on chromosome 12 q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13 q and hepatocyte nuclear factor-1 beta (HNF-1β/MODY5/TCF2) on chromosome 17cen-q. We have screened the HNF-4α, HNF-1α and HNF-1β genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T→A) and one deletion mutation (P379fsdelT) were found in the HNF-1α gene, but no MODY-associated mutations were found in the HNF-4α and HNF-1β genes. Of 67 French MODY families that we have now studied, 42 (63%) have mutations in the glucokinase gene, 14 (21%) have mutations in the HNF-1α gene, and 11 (16%) have no mutations in the HNF-4α, IPF1 and HNF-1β genes. Eleven families do not have mutations in the five known MODY genes suggesting that there is at least one additional locus that can cause MODY.