MUTATION SCREENING IN 18 CAUCASIAN FAMILIES SUGGEST THE EXISTENCE OF OTHER MODY GENES

Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulin-dependent diabetes mellitus characterised by early ons et, autosomal dominant inheritance and a primary defect in insulin sec retion. To date five MODY genes have been identified: hepatocyte nucle ar factor-4 alpha (HNF-4 alpha/MODY1/TCF14) on chromosome 20 q, glucok inase (GCK/MODY2) on chromosome 7p, hepatocyte nuclear factor-1 alpha (HNF-1 alpha/MODY3/TCF1) on chromosome 12q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13q and hepatocyte nuclear factor-1 beta (H NF-1 beta/MODY5/TCF2) on chromosome 17cen-q. We have screened the HNF- 4 alpha:, HNF-1 alpha and HNF-1 beta genes in members of 18 MODY kindr eds who tested negative for glucokinase mutations. Five missense (G31D , R159W, A161T, R200W, R271W), one substitution at the splice donor si te of intron 5 (IVS5nt + 2T --> A) and one deletion mutation (P379fsde lT) were found in the HNF-1 alpha gene, but no MODY-associated mutatio ns were found in the HNF-4 alpha and HNF-1 beta genes. Of 67 French MO DY families that we have now studied, 42 (63%) have mutations in the g lucokinase gene, 14 (21%) have mutations in the HNF-1 alpha gene, and 11 (16%) have no mutations in the HNF-4 alpha, IPF1 and HNF-1 beta gen es. Eleven families do not have mutations in the five known MODY genes suggesting that there is at least one additionnal locus that can caus e MODY.