Abstract
The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has been mapped to an 850-kb interval on 5q11.2-q13.3, between the centromeric D5S823 and telomeric D5S557 markers. We report a new complex marker, Ag1-CA, that lies in this interval, whose primers produce one, two, or rarely three amplification-fragment-length variants (AFLVs) per allele. Class I chromosomes are those which amplify a single AFLV allele, and class II chromosomes are those which amplify an allele with two or three AFLVs. Ag1-CA shows highly significant allelic association with type I SMA in both the French Canadian (Hôpital Sainte-Justine [HSJ]) and American (Ohio State University [OSU]) populations (P<.0001). Significant association between the Ag1-CA genotype and disease severity was also observed. Type I patients were predominantly homozygous for class I chromosomes (P=.0003 OSU; P=.0012 HSJ), whereas the majority of type II patients were heterozygous for class I and II chromosomes (P=.0014 OSU; P=.001 HSJ). There was no significant difference in Ag1-CA genotype frequencies between type III patients (P=.5 OSU; P=.25 HSJ) and the paired normal chromosomes from both carrier parents. Our results indicate that Ag1-CA is the most closely linked marker to SMA and defines the critical candidate-gene region. Finally, we have proposed a model that should be taken into consideration when screening candidate SMA genes.
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- Brahe C., Velonà I., van der Steege G., Zappata S., van de Veen A. Y., Osinga J., Tops C. M., Fodde R., Khan P. M., Buys C. H. Mapping of two new markers within the smallest interval harboring the spinal muscular atrophy locus by family and radiation hybrid analysis. Hum Genet. 1994 May;93(5):494–501. doi: 10.1007/BF00202811. [DOI] [PubMed] [Google Scholar]
- Brzustowicz L. M., Lehner T., Castilla L. H., Penchaszadeh G. K., Wilhelmsen K. C., Daniels R., Davies K. E., Leppert M., Ziter F., Wood D. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. 1990 Apr 5;344(6266):540–541. doi: 10.1038/344540a0. [DOI] [PubMed] [Google Scholar]
- Burghes A. H., Ingraham S. E., Kóte-Jarai Z., Rosenfeld S., Herta N., Nadkarni N., DiDonato C. J., Carpten J., Hurko O., Florence J. Linkage mapping of the spinal muscular atrophy gene. Hum Genet. 1994 Mar;93(3):305–312. doi: 10.1007/BF00212028. [DOI] [PubMed] [Google Scholar]
- Burghes A. H., Ingraham S. E., McLean M., Thompson T. G., McPherson J. D., Kote-Jarai Z., Carpten J. D., DiDonato C. J., Ikeda J. E., Surh L. A multicopy dinucleotide marker that maps close to the spinal muscular atrophy gene. Genomics. 1994 May 15;21(2):394–402. doi: 10.1006/geno.1994.1282. [DOI] [PubMed] [Google Scholar]
- Dana S., Wasmuth J. J. Linkage of the leuS, emtB, and chr genes on chromosome 5 in humans and expression of human genes encoding protein synthetic components in human--Chinese hamster hybrids. Somatic Cell Genet. 1982 Mar;8(2):245–264. doi: 10.1007/BF01538680. [DOI] [PubMed] [Google Scholar]
- Francis M. J., Morrison K. E., Campbell L., Grewal P. K., Christodoulou Z., Daniels R. J., Monaco A. P., Frischauf A. M., McPherson J., Wasmuth J. A contig of non-chimaeric YACs containing the spinal muscular atrophy gene in 5q13. Hum Mol Genet. 1993 Aug;2(8):1161–1167. doi: 10.1093/hmg/2.8.1161. [DOI] [PubMed] [Google Scholar]
- Gilliam T. C., Brzustowicz L. M., Castilla L. H., Lehner T., Penchaszadeh G. K., Daniels R. J., Byth B. C., Knowles J., Hislop J. E., Shapira Y. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature. 1990 Jun 28;345(6278):823–825. doi: 10.1038/345823a0. [DOI] [PubMed] [Google Scholar]
- Gilliam T. C., Freimer N. B., Kaufmann C. A., Powchik P. P., Bassett A. S., Bengtsson U., Wasmuth J. J. Deletion mapping of DNA markers to a region of chromosome 5 that cosegregates with schizophrenia. Genomics. 1989 Nov;5(4):940–944. doi: 10.1016/0888-7543(89)90138-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hudson T. J., Engelstein M., Lee M. K., Ho E. C., Rubenfield M. J., Adams C. P., Housman D. E., Dracopoli N. C. Isolation and chromosomal assignment of 100 highly informative human simple sequence repeat polymorphisms. Genomics. 1992 Jul;13(3):622–629. doi: 10.1016/0888-7543(92)90133-d. [DOI] [PubMed] [Google Scholar]
- Kleyn P. W., Wang C. H., Lien L. L., Vitale E., Pan J., Ross B. M., Grunn A., Palmer D. A., Warburton D., Brzustowicz L. M. Construction of a yeast artificial chromosome contig spanning the spinal muscular atrophy disease gene region. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6801–6805. doi: 10.1073/pnas.90.14.6801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Ledbetter S. A., Nelson D. L., Warren S. T., Ledbetter D. H. Rapid isolation of DNA probes within specific chromosome regions by interspersed repetitive sequence polymerase chain reaction. Genomics. 1990 Mar;6(3):475–481. doi: 10.1016/0888-7543(90)90477-c. [DOI] [PubMed] [Google Scholar]
- Lien L. L., Boyce F. M., Kleyn P., Brzustowicz L. M., Menninger J., Ward D. C., Gilliam T. C., Kunkel L. M. Mapping of human microtubule-associated protein 1B in proximity to the spinal muscular atrophy locus at 5q13. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7873–7876. doi: 10.1073/pnas.88.17.7873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MacKenzie A., Roy N., Besner A., Mettler G., Jacob P., Korneluk R., Surh L. Genetic linkage analysis of Canadian spinal muscular atrophy kindreds using flanking microsatellite 5q13 polymorphisms. Hum Genet. 1993 Jan;90(5):501–504. doi: 10.1007/BF00217448. [DOI] [PubMed] [Google Scholar]
- Mankoo B. S., Sherrington R., De La Concha A., Kalsi G., Curtis D., Melmer G., Gurling H. M. Two microsatellite polymorphisms at the D5S39 locus. Nucleic Acids Res. 1991 Apr 25;19(8):1963–1963. doi: 10.1093/nar/19.8.1963-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Melki J., Abdelhak S., Sheth P., Bachelot M. F., Burlet P., Marcadet A., Aicardi J., Barois A., Carriere J. P., Fardeau M. Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature. 1990 Apr 19;344(6268):767–768. doi: 10.1038/344767a0. [DOI] [PubMed] [Google Scholar]
- Melki J., Lefebvre S., Burglen L., Burlet P., Clermont O., Millasseau P., Reboullet S., Bénichou B., Zeviani M., Le Paslier D. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science. 1994 Jun 3;264(5164):1474–1477. doi: 10.1126/science.7910982. [DOI] [PubMed] [Google Scholar]
- Melki J., Sheth P., Abdelhak S., Burlet P., Bachelot M. F., Lathrop M. G., Frezal J., Munnich A. Mapping of acute (type I) spinal muscular atrophy to chromosome 5q12-q14. The French Spinal Muscular Atrophy Investigators. Lancet. 1990 Aug 4;336(8710):271–273. doi: 10.1016/0140-6736(90)91803-i. [DOI] [PubMed] [Google Scholar]
- Morrison K. E., Daniels R. J., Suthers G. K., Flynn G. A., Francis M. J., Buckle V. J., Davies K. E. High-resolution genetic map around the spinal muscular atrophy (SMA) locus on chromosome 5. Am J Hum Genet. 1992 Mar;50(3):520–527. [PMC free article] [PubMed] [Google Scholar]
- Pearn J. Classification of spinal muscular atrophies. Lancet. 1980 Apr 26;1(8174):919–922. doi: 10.1016/s0140-6736(80)90847-8. [DOI] [PubMed] [Google Scholar]
- Riley J., Butler R., Ogilvie D., Finniear R., Jenner D., Powell S., Anand R., Smith J. C., Markham A. F. A novel, rapid method for the isolation of terminal sequences from yeast artificial chromosome (YAC) clones. Nucleic Acids Res. 1990 May 25;18(10):2887–2890. doi: 10.1093/nar/18.10.2887. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Simard L. R., Prescott G., Rochette C., Morgan K., Lemieux B., Mathieu J., Melançon S. B., Vanasse M. Linkage disequilibrium analysis of childhood-onset spinal muscular atrophy (SMA) in the French-Canadian population. Hum Mol Genet. 1994 Mar;3(3):459–463. doi: 10.1093/hmg/3.3.459. [DOI] [PubMed] [Google Scholar]
- Simard L. R., Vanasse M., Rochette C., Morgan K., Lemieux B., Melançon S. B., Labuda D. Linkage study of chronic childhood-onset spinal muscular atrophy (SMA): confirmation of close linkage to D5S39 in French Canadian families. Genomics. 1992 Sep;14(1):188–190. doi: 10.1016/s0888-7543(05)80305-2. [DOI] [PubMed] [Google Scholar]
- Smith C. A. Chi-squared tests with small numbers. Ann Hum Genet. 1986 May;50(Pt 2):163–167. doi: 10.1111/j.1469-1809.1986.tb01035.x. [DOI] [PubMed] [Google Scholar]
- Soares V. M., Brzustowicz L. M., Kleyn P. W., Knowles J. A., Palmer D. A., Asokan S., Penchaszadeh G. K., Munsat T. L., Gilliam T. C. Refinement of the spinal muscular atrophy locus to the interval between D5S435 and MAP1B. Genomics. 1993 Feb;15(2):365–371. doi: 10.1006/geno.1993.1069. [DOI] [PubMed] [Google Scholar]
- Thompson T. G., Morrison K. E., Kleyn P., Bengtsson U., Gilliam T. C., Davies K. E., Wasmuth J. J., McPherson J. D. High resolution physical map of the region surrounding the spinal muscular atrophy gene. Hum Mol Genet. 1993 Aug;2(8):1169–1176. doi: 10.1093/hmg/2.8.1169. [DOI] [PubMed] [Google Scholar]
- Wirth B., Pick E., Leutner A., Dadze A., Voosen B., Knapp M., Piechaczek-Wappenschmidt B., Rudnik-Schöneborn S., Schönling J., Cox S. Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 CEPH families using 15 polymorphic loci in the region 5q11.2-q13.3. Genomics. 1994 Mar 1;20(1):84–93. doi: 10.1006/geno.1994.1130. [DOI] [PubMed] [Google Scholar]
- Wirth B., Voosen B., Röhrig D., Knapp M., Piechaczek B., Rudnik-Schöneborn S., Zerres K. Fine mapping and narrowing of the genetic interval of the spinal muscular atrophy region by linkage studies. Genomics. 1993 Jan;15(1):113–118. doi: 10.1006/geno.1993.1018. [DOI] [PubMed] [Google Scholar]