Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1989 Feb;44(2):255–263.

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 1, L A Sandkuyl 1, J Ott 1, S P Daiger 1, M Pollack 1, W E O'Brien 1, A L Beaudet 1
PMCID: PMC1715397  PMID: 2563195

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.

Full text

PDF
255

Images in this article

258Figure 1
on p.258
259Figure 2
on p.259

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Berciano J. Olivopontocerebellar atrophy. A review of 117 cases. J Neurol Sci. 1982 Feb;53(2):253–272. doi: 10.1016/0022-510x(82)90011-9. [DOI] [PubMed] [Google Scholar]
  2. Board P. G., Chapple R., Coggan M. Haplotypes of the coagulation factor XIII A subunit locus in normal and deficient subjects. Am J Hum Genet. 1988 May;42(5):712–717. [PMC free article] [PubMed] [Google Scholar]
  3. Braverman M. S. An algorithm to improve the computational efficiency of genetic linkage analysis. Comput Biomed Res. 1985 Feb;18(1):24–36. doi: 10.1016/0010-4809(85)90004-7. [DOI] [PubMed] [Google Scholar]
  4. Currier R. D., Glover G., Jackson J. F., Tipton A. C. Spinocerebellar ataxia: study of a large kindred. I. General information and genetics. Neurology. 1972 Oct;22(10):1040–1043. doi: 10.1212/wnl.22.9.1040. [DOI] [PubMed] [Google Scholar]
  5. Fuscoe J. C., Fenwick R. G., Jr, Ledbetter D. H., Caskey C. T. Deletion and amplification of the HGPRT locus in Chinese hamster cells. Mol Cell Biol. 1983 Jun;3(6):1086–1096. doi: 10.1128/mcb.3.6.1086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Haines J. L., Schut L. J., Weitkamp L. R., Thayer M., Anderson V. E. Spinocerebellar ataxia in a large kindred: age at onset, reproduction, and genetic linkage studies. Neurology. 1984 Dec;34(12):1542–1548. doi: 10.1212/wnl.34.12.1542. [DOI] [PubMed] [Google Scholar]
  7. Haines J. L., Trofatter J. A. Multipoint linkage analysis of spinocerebellar ataxia and markers on chromosome 6. Genet Epidemiol. 1986;3(6):399–405. doi: 10.1002/gepi.1370030604. [DOI] [PubMed] [Google Scholar]
  8. Hyldig-Nielsen J. J., Morling N., Odum N., Ryder L. P., Platz P., Jakobsen B., Svejgaard A. Restriction fragment length polymorphism of the HLA-DP subregion and correlations to HLA-DP phenotypes. Proc Natl Acad Sci U S A. 1987 Mar;84(6):1644–1648. doi: 10.1073/pnas.84.6.1644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jackson J. F., Currier R. D., Terasaki P. I., Morton N. E. Spinocerebellar ataxia and HLA linkage: risk prediction by HLA typing. N Engl J Med. 1977 May 19;296(20):1138–1141. doi: 10.1056/NEJM197705192962003. [DOI] [PubMed] [Google Scholar]
  10. Koeppen A. H., Barron K. D. The neuropathology of olivopontocerebellar atrophy. Adv Neurol. 1984;41:13–38. [PubMed] [Google Scholar]
  11. Lamm L. U., Olaisen B. Report of the Committee on the Genetic Constitution of Chromosomes 5 and 6. Cytogenet Cell Genet. 1985;40(1-4):128–155. doi: 10.1159/000132172. [DOI] [PubMed] [Google Scholar]
  12. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Leach R., DeMars R., Hasstedt S., White R. Construction of a map of the short arm of human chromosome 6. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3909–3913. doi: 10.1073/pnas.83.11.3909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Nino H. E., Noreen H. J., Dubey D. P., Resch J. A., Namboodiri K., Elston R. C., Yunis E. J. A family with hereditary ataxia: HLA typing. Neurology. 1980 Jan;30(1):12–20. doi: 10.1212/wnl.30.1.12. [DOI] [PubMed] [Google Scholar]
  15. Nussbaum R. L., Airhart S. D., Ledbetter D. H. Expression of the fragile (X) chromosome in an interspecific somatic cell hybrid. Hum Genet. 1983;64(2):148–150. doi: 10.1007/BF00327113. [DOI] [PubMed] [Google Scholar]
  16. Ott J. A simple scheme for the analysis of HLA linkages in pedigrees. Ann Hum Genet. 1978 Oct;42(2):255–257. doi: 10.1111/j.1469-1809.1978.tb00657.x. [DOI] [PubMed] [Google Scholar]
  17. Pedersen L., Platz P., Ryder L. P., Lamm L. U., Dissing J. A linkage study of hereditary ataxias and related disorders. Evidence of heterogeneity of dominant cerebellar ataxia. Hum Genet. 1980;54(3):371–383. doi: 10.1007/BF00291585. [DOI] [PubMed] [Google Scholar]
  18. Rich S. S., Wilkie P., Schut L., Vance G., Orr H. T. Spinocerebellar ataxia: localization of an autosomal dominant locus between two markers on human chromosome 6. Am J Hum Genet. 1987 Oct;41(4):524–531. [PMC free article] [PubMed] [Google Scholar]
  19. Yakura H., Wakisaka A., Fujimoto S., Itakura K. Letter: Hereditary ataxia and HL-A. N Engl J Med. 1974 Jul 18;291(3):154–155. doi: 10.1056/NEJM197407182910314. [DOI] [PubMed] [Google Scholar]
  20. Zoghbi H. Y., Daiger S. P., McCall A., O'Brien W. E., Beaudet A. L. Extensive DNA polymorphism at the factor XIIIa (F13A) locus and linkage to HLA. Am J Hum Genet. 1988 Jun;42(6):877–883. [PMC free article] [PubMed] [Google Scholar]
  21. Zoghbi H. Y., Pollack M. S., Lyons L. A., Ferrell R. E., Daiger S. P., Beaudet A. L. Spinocerebellar ataxia: variable age of onset and linkage to human leukocyte antigen in a large kindred. Ann Neurol. 1988 Jun;23(6):580–584. doi: 10.1002/ana.410230609. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES