Human Molecular Genetics, Vol 6, 1835-1846, Copyright © 1997 by Oxford University Press
S Hofmann, M Jaksch, R Bezold, S Mertens, S Aholt, A Paprotta and KD Gerbitz
Mitochondrial (mt)DNA haplogroups in a German control group (n = 67) were
characterized by screening mitochondrial coding regions encompassing 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 haplogroups, could be
defined by characteristic polymorphic sites in mitochondrial genes.
Additional sequencing of two hypervariable segments (HVS-I and II) of the
non-coding displacement (D) loop in all control subjects revealed that
certain D loop variants were strongly correlated with lineages and
haplogroups, while others represented hotspots occurring frequently in
different haplogroups. The existence of identified lineages 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 LHON mutations at nt 3460, 11778,
14484 and/or 15257; (ii) patients suffering from Wolfram or DIDMOAD
syndrome (n = 8); (iii) MELAS patients (n = 9); (iv) a group of children,
who died from 'sudden infant death syndrome' (SIDS) (n = 9). The
distribution patterns among the haplogroups of the disease groups (LHON,
DIDMOAD and SIDS) differed considerably from the control population. LHON
and DIDMOAD were significantly under-represented in the most frequent
German haplogroup DC, but were concentrated in a mtDNA lineage defined by
polymorphisms at nt 4216 + 11251 + 16126. As this lineage diverged into two
precisely defined haplogroups, LHON and DIDMOAD could be assigned to the
two haplogroups separately. Strikingly, SIDS was often found in association
with two rare German haplogroups. MELAS patients were equally distributed
among German haplogroups and, moreover, did not reveal any accumulation of
specific D loop variants. We conclude that certain European mtDNA
haplogroups define a genetic susceptibility basis for various disorders.
ARTICLES
Population genetics and disease susceptibility: characterization of central European haplogroups by mtDNA gene mutations, correlation with D loop variants and association with disease
Institute of Clinical Chemistry, Academic Hospital Schwabing, Munich, Germany.
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