Transient but not permanent neonatal diabetes mellitus is associated with paternal uniparental isodisomy of chromosome 6

Objectives. The factors determining the pathogenesis of transient and perma nent neonatal diabetes mellitus are poorly characterized. The purpose of th is study was to examine the role of chromosome 6 in the pathogenesis of neo natal diabetes mellitus and to detect differences between these 2 phenotype s. Methods. Microsatellite markers (D6S334, D6S286, D6S310, D6S308, D6S292, D6 S311, and D6S403) and human leukocyte antigen DQ alleles were examined usin g polymerase chain reaction and DNA fragment electrophoresis in 3 patients with transient and 3 patients with permanent neonatal diabetes mellitus. Hu moral markers of islet cell autoimmunity and clinical characteristics were analyzed in the 2 groups. Results. A patient with transient neonatal diabetes mellitus (TND) and macr oglossia carrying paternal uniparental isodisomy (UPD) of chromosome 6 has been identified. The isodisomy affected the whole chromosome; no maternal c hromosome 6 sequences were detected. The permanent neonatal diabetes mellit us cases and the other 2 cases with TND did not have UPD. None of the patie nts had high-risk type 1 diabetes human leukocyte antigen DQ alleles and mo st infants were negative for islet cell-specific autoantibodies indicating that none of the 2 forms of neonatal diabetes mellitus is likely to be of a utoimmune origin. An association of TND and persistent granulocytopenia is described for the first time. Conclusions. We propose that transient and permanent forms of neonatal diab etes mellitus have different genetic background and represent different dis ease entities. TND is associated with UPD of chromosome 6 suggesting that a n imprinted gene on chromosome 6 is responsible for this phenotype. It seem s that 2 copies of the paternal allele are necessary for the development of TND; therefore, it is likely that overexpression of a putative gene locate d on chromosome 6 alters pancreatic beta-cell maturation and insulin secret ion.