Association between Ag1-CA alleles and severity of autosomal recessive proximal spinal muscular atrophy.
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.
DiDonato
C J
CJ
Department of Molecular Genetics, Ohio State University, Columbus 43210.
Morgan
K
K
Carpten
J D
JD
Fuerst
P
P
Ingraham
S E
SE
Prescott
G
G
McPherson
J D
JD
Wirth
B
B
Zerres
K
K
Hurko
O
O
D000483:Alleles; D001483:Base Sequence; D002170:Canada / Q000453:epidemiology; D002869:Chromosome Aberrations / Q000235:genetics*; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003360:Cosmids; D005260:Female; D005602:France / Q000208:ethnology; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D006822:Hybrid Cells; D008297:Male; D008969:Molecular Sequence Data; D009134:Muscular Atrophy, Spinal / Q000145:classification / Q000208:ethnology / Q000235:genetics* / Q000473:pathology*; D016133:Polymerase Chain Reaction; D016324:Sequence Tagged Sites
D005819:Genetic Markers