Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1995 May;56(5):1088–1095.

Random search for shared chromosomal regions in four affected individuals: the assignment of a new hereditary ataxia locus.

K Nikali 1, A Suomalainen 1, J Terwilliger 1, T Koskinen 1, J Weissenbach 1, L Peltonen 1
PMCID: PMC1801458  PMID: 7726163

Abstract

Infantile-onset spinocerebellar ataxia (IOSCA) is an autosomal recessively inherited progressive neurological disorder of unknown etiology. This ataxia, identified so far only in the genetically isolated Finnish population, does not share gene locus with any of the previously identified hereditary ataxias, and a random mapping approach was adopted to assign the IOSCA locus. Based on the assumption of one founder mutation, a primary screening of the genome was performed using samples from just four affected individuals in two consanguineous pedigrees. The identification of a shared chromosomal region in these four patients provided the first evidence that the IOSCA gene locus is on chromosome 10q23.3-q24.1, which was confirmed by conventional linkage analysis in the complete family material. Strong linkage disequilibrium observed between IOSCA and the linked markers was utilized to define accurately the critical chromosomal region. The results showed the power of linkage disequilibrium in the locus assignment of diseases with very limited family materials.

Full text

PDF
1095

Selected References

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

  1. Ben Hamida C., Doerflinger N., Belal S., Linder C., Reutenauer L., Dib C., Gyapay G., Vignal A., Le Paslier D., Cohen D. Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat Genet. 1993 Oct;5(2):195–200. doi: 10.1038/ng1093-195. [DOI] [PubMed] [Google Scholar]
  2. Cocozza S., Antonelli A., Campanella G., Cavalcanti F., De Michele G., Di Donato S., Filla A., Monticelli A., Pianese L., Piccinelli A. Evidence of a genetic marker associated with early onset in Friedreich's ataxia. J Neurol. 1993;240(4):254–256. doi: 10.1007/BF00818715. [DOI] [PubMed] [Google Scholar]
  3. Deloukas P., Dauwerse J. G., Moschonas N. K., van Ommen G. J., van Loon A. P. Three human glutamate dehydrogenase genes (GLUD1, GLUDP2, and GLUDP3) are located on chromosome 10q, but are not closely physically linked. Genomics. 1993 Sep;17(3):676–681. doi: 10.1006/geno.1993.1389. [DOI] [PubMed] [Google Scholar]
  4. Fan Y. S., Sasi R., Lee C., Winter J. S., Waterman M. R., Lin C. C. Localization of the human CYP17 gene (cytochrome P450(17 alpha)) to 10q24.3 by fluorescence in situ hybridization and simultaneous chromosome banding. Genomics. 1992 Dec;14(4):1110–1111. doi: 10.1016/s0888-7543(05)80140-5. [DOI] [PubMed] [Google Scholar]
  5. Gatti R. A., Berkel I., Boder E., Braedt G., Charmley P., Concannon P., Ersoy F., Foroud T., Jaspers N. G., Lange K. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature. 1988 Dec 8;336(6199):577–580. doi: 10.1038/336577a0. [DOI] [PubMed] [Google Scholar]
  6. Gispert S., Twells R., Orozco G., Brice A., Weber J., Heredero L., Scheufler K., Riley B., Allotey R., Nothers C. Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23-24.1. Nat Genet. 1993 Jul;4(3):295–299. doi: 10.1038/ng0793-295. [DOI] [PubMed] [Google Scholar]
  7. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  8. Hanauer A., Chery M., Fujita R., Driesel A. J., Gilgenkrantz S., Mandel J. L. The Friedreich ataxia gene is assigned to chromosome 9q13-q21 by mapping of tightly linked markers and shows linkage disequilibrium with D9S15. Am J Hum Genet. 1990 Jan;46(1):133–137. [PMC free article] [PubMed] [Google Scholar]
  9. Harding A. E. Classification of the hereditary ataxias and paraplegias. Lancet. 1983 May 21;1(8334):1151–1155. doi: 10.1016/s0140-6736(83)92879-9. [DOI] [PubMed] [Google Scholar]
  10. Hellsten E., Vesa J., Speer M. C., Mäkelä T. P., Järvelä I., Alitalo K., Ott J., Peltonen L. Refined assignment of the infantile neuronal ceroid lipofuscinosis (INCL, CLN1) locus at 1p32: incorporation of linkage disequilibrium in multipoint analysis. Genomics. 1993 Jun;16(3):720–725. doi: 10.1006/geno.1993.1253. [DOI] [PubMed] [Google Scholar]
  11. Hästbacka J., de la Chapelle A., Kaitila I., Sistonen P., Weaver A., Lander E. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet. 1992 Nov;2(3):204–211. doi: 10.1038/ng1192-204. [DOI] [PubMed] [Google Scholar]
  12. Jodice C., Frontali M., Persichetti F., Novelletto A., Pandolfo M., Spadaro M., Giunti P., Schinaia G., Lulli P., Malaspina P. The gene for spinal cerebellar ataxia 1 (SCA1) is flanked by two closely linked highly polymorphic microsatellite loci. Hum Mol Genet. 1993 Sep;2(9):1383–1387. doi: 10.1093/hmg/2.9.1383. [DOI] [PubMed] [Google Scholar]
  13. Kawaguchi Y., Okamoto T., Taniwaki M., Aizawa M., Inoue M., Katayama S., Kawakami H., Nakamura S., Nishimura M., Akiguchi I. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994 Nov;8(3):221–228. doi: 10.1038/ng1194-221. [DOI] [PubMed] [Google Scholar]
  14. Koskinen T., Sainio K., Rapola J., Pihko H., Paetau A. Sensory neuropathy in infantile onset spinocerebellar ataxia (IOSCA). Muscle Nerve. 1994 May;17(5):509–515. doi: 10.1002/mus.880170507. [DOI] [PubMed] [Google Scholar]
  15. Koskinen T., Santavuori P., Sainio K., Lappi M., Kallio A. K., Pihko H. Infantile onset spinocerebellar ataxia with sensory neuropathy: a new inherited disease. J Neurol Sci. 1994 Jan;121(1):50–56. doi: 10.1016/0022-510x(94)90156-2. [DOI] [PubMed] [Google Scholar]
  16. Kölble K. Regional mapping of short tandem repeats on human chromosome 10: cytochrome P450 gene CYP2E, D10S196, D10S220, and D10S225. Genomics. 1993 Dec;18(3):702–704. doi: 10.1016/s0888-7543(05)80378-7. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Meehan R. R., Gosden J. R., Rout D., Hastie N. D., Friedberg T., Adesnik M., Buckland R., van Heyningen V., Fletcher J., Spurr N. K. Human cytochrome P-450 PB-1: a multigene family involved in mephenytoin and steroid oxidations that maps to chromosome 10. Am J Hum Genet. 1988 Jan;42(1):26–37. [PMC free article] [PubMed] [Google Scholar]
  19. Moir D. T., Dorman T. E., Day J. C., Ma N. S., Wang M. T., Mao J. I. Toward a physical map of human chromosome 10: isolation of 183 YACs representing 80 loci and regional assignment of 94 YACs by fluorescence in situ hybridization. Genomics. 1994 Jul 1;22(1):1–12. doi: 10.1006/geno.1994.1338. [DOI] [PubMed] [Google Scholar]
  20. Mullis K. B., Faloona F. A. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol. 1987;155:335–350. doi: 10.1016/0076-6879(87)55023-6. [DOI] [PubMed] [Google Scholar]
  21. Nikali K., Koskinen T., Suomalainen A., Pihko H., Peltonen L. Infantile onset spinocerebellar ataxia represents an allelic disease distinct from other hereditary ataxias. Pediatr Res. 1994 Nov;36(5):607–612. doi: 10.1203/00006450-199411000-00012. [DOI] [PubMed] [Google Scholar]
  22. Orr H. T., Chung M. Y., Banfi S., Kwiatkowski T. J., Jr, Servadio A., Beaudet A. L., McCall A. E., Duvick L. A., Ranum L. P., Zoghbi H. Y. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993 Jul;4(3):221–226. doi: 10.1038/ng0793-221. [DOI] [PubMed] [Google Scholar]
  23. Ott J. Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4175–4178. doi: 10.1073/pnas.86.11.4175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pandolfo M., Sirugo G., Antonelli A., Weitnauer L., Ferretti L., Leone M., Dones I., Cerino A., Fujita R., Hanauer A. Friedreich ataxia in Italian families: genetic homogeneity and linkage disequilibrium with the marker loci D9S5 and D9S15. Am J Hum Genet. 1990 Aug;47(2):228–235. [PMC free article] [PubMed] [Google Scholar]
  25. Ranum L. P., Duvick L. A., Rich S. S., Schut L. J., Litt M., Orr H. T. Localization of the autosomal dominant HLA-linked spinocerebellar ataxia (SCA1) locus, in two kindreds, within an 8-cM subregion of chromosome 6p. Am J Hum Genet. 1991 Jul;49(1):31–41. [PMC free article] [PubMed] [Google Scholar]
  26. Terwilliger J. D. A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am J Hum Genet. 1995 Mar;56(3):777–787. [PMC free article] [PubMed] [Google Scholar]
  27. Vandenplas S., Wiid I., Grobler-Rabie A., Brebner K., Ricketts M., Wållis G., Bester A., Boyd C., Måthew C. Blot hybridisation analysis of genomic DNA. J Med Genet. 1984 Jun;21(3):164–172. doi: 10.1136/jmg.21.3.164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Zheng C. J., Ma N. S., Dorman T. E., Wang M. T., Braunschweiger K., Soares L., Schuster M. K., Rothschild C. B., Bowden D. W., Torrey D. Development of 124 sequence-tagged sites and cytogenetic localization of 217 cosmids for human chromosome 10. Genomics. 1994 Jul 1;22(1):55–67. doi: 10.1006/geno.1994.1345. [DOI] [PubMed] [Google Scholar]

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

RESOURCES