Assignment of autosomal dominant spinocerebellar ataxia (SCA1) centromeric to the HLA region on the short arm of chromosome 6, using multilocus linkage analysis.
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.
Zoghbi
H Y
HY
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030.
Sandkuyl
L A
LA
Ott
J
J
Daiger
S P
SP
Pollack
M
M
O'Brien
W E
WE
Beaudet
A L
AL
D000818:Animals; D015139:Blotting, Southern; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D006224:Cricetinae; D003412:Cricetulus; D015343:DNA Probes, HLA; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D006822:Hybrid Cells; D008297:Male; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D013132:Spinocerebellar Degenerations / Q000235:genetics*
D015343:DNA Probes, HLA; D005819:Genetic Markers; D006680:HLA Antigens