Abstract
A mitochondrial disorder may be one of the rare aetiologies
of occipital stroke. Clinical and molecular analysis has suggested
that 10% of young patients with occipital stroke have a
mitochondrial disorder and 6% harbour the mutation 3243A>G
in mitochondrial DNA (mtDNA), causing the MELAS syndrome. To identify
other possible mtDNA mutations involved, we studied mtDNA genotypes
in patients who had suffered an occipital stroke and in whom the
common pathogenic mutations in mtDNA had been excluded.
Since one systematic way of comparing mtDNA sequences is through
phylogenetic analysis, a phylogenetic network for the Finnish mtDNA
haplogroup U was constructed and used to identify differences in
mtDNA between patients and controls. The usefulness of conformation
sensitive gel electrophoresis (CSGE) for analysing differences within
the coding sequence of mtDNA was also estimated.
We studied mtDNA genotypes of 29 patients with occipital stroke.
The aetiology of the stroke was assessed using the criteria of the
Baltimore-Washington Cooperative Young Stroke Study, and migraine
was diagnosed in 18 patients according to the International Headache
Society criteria. Moreover, we studied the mtDNA genotypes of 42
patients with migraine and a total of 480 population controls who
reported that they themselves and their mothers were healthy with
respect to common clinical manifestations of mtDNA disease. The
mtDNA haplogroups were detected by restriction fragment analysis
and the mtDNA structures of 14 patients with occipital stroke and
43 subjects belonging to haplogroup U were examined by CSGE. The
data acquired by CSGE were then used to construct a phylogenetic
network for the Finnish mtDNA haplogroup U.
We found CSGE to be a highly sensitive and specific method
for screening mutations and polymorphisms in mtDNA. The sequence
data on the 43 subjects belonging to the mtDNA haplogroup U were
used to construct a phylogenetic network, which was found to be
an unambiguous tree with few homoplasies that pointed to several
previously unidentified common polymorphisms. The major branch of
the network was U5, which seemed to be quite specific to the Finns.
Branches representing haplogroups U2, U4, U7 and K could also be
detected. Restriction fragment analysis of the patients with occipital
stroke revealed that all those with migraine as a probable aetiology belonged
to the mtDNA haplogroup U, suggesting that this genotype confers
a risk of occipital stroke. In addition to the five patients with
migrainous stroke, we analyzed the complete mtDNA coding sequences
of nine other patients with occipital stroke belonging to haplogroup
U by CSGE. Analysis of the phylogenetic network revealed an association
of migrainous stroke with mtDNA haplogroup U5. Furthermore, the
distribution of the mtDNA genotypes in the patients with stroke
differed from that found in the controls. Four patients harboured
potentially pathogenic mutations.
CSGE proved to be an effective method for use in mitochondrial
genetics, enabling us to construct an unambiguous network for the
Finnish haplogroup U. Similar phylogenetic networks are required for
the purposes of both medical genetics and population genetics. Such
networks were found to be helpful in deciding between a rare polymorphism
and a pathogenic mutation in patients with occipital stroke. Likewise,
they enabled more detailed comparisons to be made between and within
populations and allowed more accurate phylogenetic relationships
to be determined.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-5567-4 |
| Date | 02 March 2000 |
| Creators | Finnilä, S. (Saara) |
| Publisher | University of Oulu |
| Source Sets | University of Oulu |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess, © University of Oulu, 2000 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234 |
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