POPULATION-GENETICS AND DISEASE SUSCEPTIBILITY - CHARACTERIZATION OF CENTRAL-EUROPEAN HAPLOGROUPS BY MTDNA GENE-MUTATIONS, CORRELATION WITHD-LOOP VARIANTS AND ASSOCIATION WITH DISEASE

Mitochondrial (mt)DNA haplogroups in a German control group (n = 67) w ere characterized by screening mitochondrial coding regions encompassi ng most of the ND, tRNA and cyt b genes. We used a PCR-SSCP screening approach followed by direct sequencing of polymorphic mtDNA fragments. Five major mtDNA lineages, diverging in at least nine different haplo groups, could be defined by characteristic polymorphic sites in mitoch ondrial genes. Additional sequencing of two hypervariable segments (HV S-I and II) of the non-coding displacement (D) loop in all control sub jects revealed that certain D loop variants were strongly correlated w ith lineages and haplogroups, while others represented hotspots occurr ing frequently in different haplogroups. The existence of identified l ineages and haplogroups received support from data in the literature, obtained by use of different approaches. Subsequently, we investigated four disease groups for association with these haplogroups: (i) LHON patients (n = 55) carrying at least one of the primary/intermediate LH ON mutations at nt 3460, 11778, 14484 and/or 15257; (ii) patients suff ering from Wolfram or DIDMOAD syndrome (n = 8); (iii) MELAS patients ( n = 9); (iv) a group of children, who died from 'sudden infant death s yndrome' (SIDS) (n = 9). The distribution patterns among the haplogrou ps of the disease groups (LHON, DIDMOAD and SIDS) differed considerabl y from the control population. LHON and DIDMOAD were significantly und er-represented in the most frequent German haplogroup D-C, but were co ncentrated in a mtDNA lineage defined by polymorphisms at nt 4216+1125 1+16126. As this lineage diverged into two precisely defined haplogrou ps, LHON and DIDMOAD could be assigned to the two haplogroups separate ly. Strikingly SIDS was often found in association with two rare Germa n haplogroups. MELAS patients were equally distributed among German ha plogroups and, moreover, did not reveal any accumulation of specific D loop variants. We conclude that certain European mtDNA haplogroups de fine a genetic susceptibility basis for various disorders.