A RAPID SCREENING METHOD FOR HEPATOCYTE NUCLEAR FACTOR-1-ALPHA FRAMESHIFT MUTATIONS - PREVALENCE IN MATURITY-ONSET DIABETES OF THE YOUNG AND LATE-ONSET NON-INSULIN-DEPENDENT DIABETES

Non-insulin dependent diabetes (NIDDM) is a polygenic heterogeneous di sorder of glucose homeostasis. Maturity-onset diabetes of the young (M ODY) is a monogenic subtype of NIDDM characterised by early-onset (< 2 5 years) and autosomal dominant inheritance. Mutations in the hepatocy te nuclear factor 1 alpha (HNF-1 alpha) gene have recently been shown to cause MODY. The incidence of mutations in this gene in MODY and lat e-onset NIDDM is not known. We have developed a rapid specific polymer ase chain reaction test for HNF-1 alpha mutations; this test involves the use of fluorescently labelled forward primers and modified reverse primers to detect length polymorphisms resulting from frameshift muta tions. With this method, we have screened 102 MODY probands, viz. 60 d efined according to strict diagnostic criteria (autosomal dominant inh eritance and at least one member diagnosed age < 25 years) and 95 late -onset NIDDM probands (diagnosed 35-70 years with greater than or equa l to 1 affected relative), for the presence of 9 known HNF-1 alpha fra meshift mutations, including 6 that occur at two sites for recurring m utation (residues 291/292 and 379). Mutations were detected in 11 of t he strictly defined MODY probands and one mutation was also found in a single subject with early-onset NIDDM but no family history of the di sease. The HNF-1 alpha frameshift mutations were not detected in any l ate-onset NIDDM subjects, suggesting these mutations do not have a maj or role in the pathogenesis of NIDDM. Our results indicate that the pr evalence of the nine frameshift mutations in strictly defined UK MODY is 18%, with the P291fsinsC mutation alone having a frequency of 13%.