WOLFRAM (DIDMOAD) SYNDROME AND LEBER HEREDITARY OPTIC NEUROPATHY (LHON) ARE ASSOCIATED WITH DISTINCT MITOCHONDRIAL-DNA HAPLOTYPES

Because Wolfram (or DIDMOAD) syndrome is supposed to be a mitochondria l (mt)-mediated disease, we investigated a group of eight DIDMOAD pati ents with respect to point mutations of the mtDNA thus far described a s being associated with defined mitochondrial disorders such as MELAS, MERRF, and LHON. Furthermore, to screen DIDMOAD patients for other mt DNA defects we used Southern blot analysis to detect mtDNA length muta tions and rearrangements as well as PCR-SSCP and direct sequencing to screen all ND genes (complex I of the respiratory chain), the 22 tRNAs , and a part of the cyt b gene for unknown mutations. As a disease con trol group, 17 LHON patients (harboring one of the primary LHON mutati ons) were included in this study because of the overlapping clinical s ymptoms (optic atrophy) in both syndromes. We compared mtDNA variants identified in DIDMOAD patients with those found in LHON patients as we ll as in a control group consisting of 67 healthy German blood donors. In total, the control group was characterized by 29 polymorphic sites in ND and tRNA genes that define certain major Caucasian haplotypes. me found that a cluster of nucleotide exchanges at nucleotide position s (nps) 4216 and 11,251 roughly discriminates controls (12/67 controls , 18%) from the disease groups (6/8 DIDMOAD patients, 75%; 10/17 LHON patients, 59%). All 4216-positive LHON patients (10 patients) were con centrated in a haplogroup defined by additional exchanges at nps 10,39 8, 12,612, and 13,708 (haplogroup A), while the bulk of 4216-positive DIDMOAD patients (5 patients) were found in a distinct haplogroup cons isting of nucleotide exchanges at nps 4917, 10,463, 13,368, 14,233, an d 15,928. The frequencies of both haplogroups were significantly lower in the control group versus the respective disease groups. A more det ailed analysis was performed by sequencing the two hypervariable regio ns of the noncoding D-loop region from patients and controls and corro borated the ranging in the two major haplogroups. Thus, the different clinical features of the mitochondrial disease groups investigated her e corresponded to different clusters of mtDNA variants, which might ac t as predisposing haplotypes, increasing the risk for disease. (C) 199 7 Academic Press