Association between Ag1-CA alleles and severity of autosomal recessive proximal spinal muscular atrophy

Am J Hum Genet. 1994 Dec;55(6):1218-29.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Base Sequence
  • Canada / epidemiology
  • Chromosome Aberrations / genetics*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 5 / genetics
  • Cosmids
  • Female
  • France / ethnology
  • Genetic Linkage
  • Genetic Markers / genetics
  • Haplotypes
  • Humans
  • Hybrid Cells
  • Male
  • Molecular Sequence Data
  • Muscular Atrophy, Spinal / classification
  • Muscular Atrophy, Spinal / ethnology
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / pathology*
  • Polymerase Chain Reaction
  • Sequence Tagged Sites


  • Genetic Markers

Associated data

  • GENBANK/U19233