Assignment of Autosomal Dominant Spinocerebellar Ataxia (SCA1)
Centromeric to the HLA Region on the Short Arm of Chromosome 6,
Using Multilocus Linkage Analysis
H.Y. Zoghbi, L.A. Sandkuyl, J. Ott, S.P. Daiger,
M. Pollack, W.E. O'Brien, A.L. Beaudet
American Journal of Human Genetics , 44(2), 255--263 (1989 Feb)
Abstract
A 7-generation kindred with the HLA-linked form of spinocerebellar
ataxia (SCA1) was studied to determine whether the SCA1 gene maps
centromeric or telomeric to the HLA loci. The DNA markers flanking
the HLA-(A-B) region were used for polymorphism studies and
multilocus linkage analysis. These two markers are the cDNA for the
beta-subunit of HLA-DP, which is centromeric to HLA-(A-B), and the
cDNA for coagulation factor XIIIa (F13A), which is telomeric to
HLA-(A-B). Haplotypes were constructed using multiple polymorphisms
for these two DNA markers, and pairwise linkage analysis revealed a
maximum lod score of 2.18 for SCA1 versus HLA-DP at a recombination
fraction of .05 and a maximum lod score of 0 for SCA1 versus F13A at
a recombination fraction of .50. A possible crossover between
HLA-(A-B) and HLA-DP was identified, but lack of samples from key
individuals hampered the analysis. To clarify the phase and improve
the analysis, the two chromosomes 6 for the crossover individual
were separated in somatic cell hybrids. The results strongly favored
the probability that the crossover occurred between HLA-(A-B-DR) and
HLA-DP with SCA1 segregating with HLA-DP, consistent with a location
centromeric to HLA-(A-B). Multilocus linkage analysis was used to
evaluate further the location of SCA1 relative to F13A, HLA-(A-B),
and HLA-DP; the results indicated that the SCA1 gene locus is
centromeric to HLA-DP with odds of 46:1 favoring this most likely
location over the second most likely location, i.e., telomeric to
HLA-(A-B) between the HLA complex and F13A.
