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 Agl-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.
|Original language||English (US)|
|Number of pages||12|
|Journal||American Journal of Human Genetics|
|State||Published - Dec 1994|
ASJC Scopus subject areas