Localisation of a gene for transient neonatal diabetes mellitus to an 18.72 cR(3000) (similar to 5.4 Mb) interval on chromosome 6q

Transient neonatal diabetes mellitus (TNDM) is a rare condition which prese nts with intrauterine growth retardation, dehydration, and failure to thriv e. The condition spontaneously resolves before I year of age but predispose s patients to type 2 diabetes later in life. We have previously shown that, in some cases, TNDM is associated with paternal uniparental disomy (UPD) o f chromosome 6 and suggested that an imprinted gene responsible for TNDM li es within a region of chromosome 6q. By analysing three families, two with duplications (family A and patient C) and one with several affected subject s with normal karyotypes (family B), we have further defined the TNDM criti cal region. In patient A, polymorphic microsatellite repeat analysis identi fied a duplicated region of chromosome 6, flanked by markers D6S472 and D6S 311. This region was identified on the Sanger Centre's chromosome 6 radiati on hybrid map (http://www.sanger.ac.uk/HGP/Chr6) and spanned approximately 60 cR(3000). Using markers within the region, 418 unique P1 derived artific ial chromosomes (PACs) have been isolated and used to localise the distal b reakpoints of the two duplications. Linkage analysis of the familial case w ith a normal karyotype identified a recombination within the critical regio n. This recombination has been identified on the radiation hybrid map and d efines the proximal end of the region of interest. We therefore propose tha t an imprinted gene for TNDM lies within an 18.72 cR(3000) (similar to 5.4 Mb) interval on chromosome 6q24.1-q24.3 between markers D6S1699 and D6S1010 .