Identification of strong allele association and candidate cDNAs for the Spinal Muscular Atrophy gene
- Dept. of Neurology, Columbus, OH (United States); and others
The gene responsible for Spinal Muscular Atrophy (SMA) has been localized to a 850kb region on chromosome 5q11.2-q13.3 between the loci D5S823 and K5S557. This region is extremely complex and consequently the isolation of candidate cDNAs has been difficult. We have isolated a unique dinucleotide repeat marker, Ag1-CA, that maps to this interval and identifies 1, 2 or rarely 3 alleles per chromosome. We have conducted allelic association studies to identify the minimal region that should be searched for candidate cDNAs. Ag1-CA demonstrates the strongest allelic association observed to date with SMA (p<10{sup -4}) in at least 3 populations: French Canadian (HSJ), German and American (OSU) and acts to core two consensus haplotypes observed in the French Canadian population. Class 1 (single Ag1-CA allele) and Class II (2 or 3 alleles) chromosomes were found to be significantly different in Type 1 (p=.0003 OSU; .0012 HSJ) and Type II (p=.001 OSU; .001 HSJ) patients and there was no difference between Type III and normals (p=.5 OSU; .25 HSJ). 72% of Type I patients are Class I homozygotes while 78% of Type II patients are Class I/Class II heterozygotes indicating that the allele class marks the clinical severity of this disease. In addition, deletions may be responsible for the allele loss seen in 9% of German Type I SMA families where one parent fails to contribute any alleles of this locus to the affected child. Given the above results and the fact that we have shown this region to be unstable and frequently deleted in YACs, we have cloned greater than 500 kb surrounding the Ag1-CA locus in cosmids and P1 clones with maximum redundancy. Partial sequence data from one clone has revealed an ORF and no strong similarities to known sequences. In order to isolate the full length transcript we have used this clone in cDNA hybridizations and isolated an additional 8 cDNAs. Currently we are analyzing this cDNA in our patient population to determine if it is the SMA gene.
- OSTI ID:
- 133385
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0113
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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