Expanded CAG repeats in spinocerebellar ataxia (SCA1) segregate with distinct haplotypes in South African families |
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Authors: | R S Ramesar Soraya Bardien Peter Beighton Alan Bryer |
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Institution: | (1) MRC Medical Genetics Research Unit, Department of Human Genetics, University of Cape Town Medical School, Anzio Road, Observatory 7925, South Africa Tel.: +27 21 406 6506; Fax: +27 21 47 7703; e-mail: rr@anat.uct.ac.za, ZA;(2) Department of Neurology, Groote Schuur Hospital, Cape Town, South Africa, ZA |
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Abstract: | The autosomal dominant late onset spinocerebellar ataxias (SCAs) are genetically heterogeneous. Three genes, SCA1 on 6p,
SCA2 on 12q and MJD1 on 14q, have been isolated for SCA1, SCA2 and Machado-Joseph disease (MJD), respectively. In these three
autosomal dominant disorders the mutation is an expanded CAG repeat. Evidence for heterogeneity in families not linked to
the SCA1, SCA2 and MJD loci is provided by the mapping of SCA loci to chromosomes 16q, 11cen and 3p. A total of 14 South African
kindreds and 22 sporadic individuals with SCA were investigated for the expanded SCA1 and MJD repeats. None of the families
nor the sporadic individuals showed expansion of the MJD repeat. Expanded SCA1 and CAG repeats were found to cosegregate with
the disorder in six of the families tested and were also observed in one sporadic individual with a negative family history
of SCA. The use of the microsatellite markers D6S260, D6S89 and D6S274 provided evidence that the expanded SCA1 repeats segregated
with three distinct haplotypes in the six families. Use of the highly polymorphic tightly linked microsatellite markers is
still important as this stage, particularly where this coincides with the possibility of a homozygous genotype with the trinucleotide
repeat marker. Importantly, our molecular findings indicate: (1) an absence of MJD expanded repeats underlying SCA; (2) the
major disease in this group is due to mutations in the SCA1 gene; and (3) the familial disorder in the majority population
group (i.e. mixed ancestry) in the Western Cape region of South Africa is most likely to be the result of two distinct founder
events.
Received: 4 November 1996 / Accepted: 6 February 1997 |
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