ANALYSIS OF THE MITOCHONDRIAL-DNA FROM PATIENTS WITH WOLFRAM (DIDMOAD) SYNDROME

Wolfram or DIDMOAD (Diabetes Insipidus, Diabetes Melitus, Optic Atroph y and Deafness) syndrome, which has long been known as an autosomal-re cessive disorder, has recently been proposed to be a mitochondrial-med iated disease with either a nuclear or a mitochondrial genetic backgro und. The phenotypic characteristics of the syndrome resemble those fou nd in other mitochondrial (mt)DNA mediated disorders such as Leber's h ereditary optic neuropathy (LHON) or maternally inherited diabetes and deafness (MIDD). Therefore, we looked for respective mtDNA alteration s in blood samples from 7 patients with DIDMOAD syndrome using SSCP-an alysis of PCR-amplified fragments, encompassing all mitochondrial ND a nd tRNA genes, followed by direct sequencing. Subsequently, we compare d mtDNA variants identified in this disease group with those detected in a group of LHON patients (n = 17) and in a group of 69 healthy cont rols. We found that 4/7 (57%) DIDMOAD patients harbored a specific set of point mutations in tRNA and ND genes including the so-called class II or secondary LHON mutations at nucleotide positions (nps) 4216 and 4917 (haplogroup B). In contrast, LHON-patients were frequently (10/1 7, 59%) found in association with another cluster of mtDNA variants in cluding the secondary LHON mutations at nps 4216 and 13708 and further mtDNA polymorphisms in ND genes (haplogroup A), overlapping with hapl ogroup B only by variants at nps 4216 and 11251. The frequencies of bo th haplogroups were significantly lower in the control group versus th e respective disease groups. We propose that haplogroup B represents a susceptibility factor for DIDMOAD which, by interaction with further exogeneous or genetic factors, might increase the risk for disease.