title: Allelic association and deletions in autosomal recessive proximal spinal muscular atrophy: association of marker genotype with disease severity and candidate cDNAs.
abstract: The candidate region for spinal muscular atrophy (SMA) has been defined as a 750 kb interval on 5q13. In this study, we performed allelic association studies in 154 German SMA families with the multicopy markers Ag1-CA (D5S1556); C212 (D5F149S1/S2) and correlated genotype data with deletion of candidate genes. Both multicopy markers recognize 0-3 alleles pro chromosome. Deletions were detected for all copies of the markers Ag1-CA (C272) and C212 in 13 of 88 (15%) type I SMA patients and three of 48 (6%) type II patients. In all informative cases, the deletion was inherited from one parent. In two further cases (one type I and one type III SMA), de novo deletions of only one copy of Ag1-CA and C212 were found. In both cases the patients were homozygously deleted for the survival motor neuron (SMN) gene (exons 7 and 8) but only the type I SMA patient was deleted for the neuronal apoptosis inhibitory protein (NAIP) gene (exons 5 and 6). A third case (type II SMA) showed de novo deletion of SMN, but not of Ag1-CA, C212 and NAIP. Specific alleles of Ag1-CA and C212 showed significant association with SMA, particularly in type I SMA. When the number of marker copies defines genotypes, 1,1 (one allele on each chromosome) is found to be increased in type I SMA (50%) and 1,2 (one allele on one chromosome and two alleles on the other one) in type II SMA (60%). The 2,2 genotype (two alleles on each chromosome) was found in 4% of type I and II patients. By comparison, pooled normal genotype frequencies were 20, 44 and 36%, respectively. These results suggest a strong correlation between genotype and severity of disease. Based on these data we propose a model which indicates that type I SMA patients are composed of two severe alleles, type II of a mild and a severe, and type III of two mild alleles. Correlation of Ag1-CA genotype with deletion of the XS2G3/NAIP genes indicates that most patients with a deletion have a 1,1 genotype. Owing to the physical proximity of these markers, we propose that a large deletion occurs on type I SMA chromosomes that removes DNA between C212 and XS2G3/NAIP and that type II SMA results from compound heterozygosity for mild (small deletion) and severe mutations.
authors.affiliation: Institute of Human Genetics, Bonn, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Wirth
authors.forename: E
authors.initials: E
authors.lastname: Hahnen
authors.forename: K
authors.initials: K
authors.lastname: Morgan
authors.forename: C J
authors.initials: CJ
authors.lastname: DiDonato
authors.forename: A
authors.initials: A
authors.lastname: Dadze
authors.forename: S
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.forename: L R
authors.initials: LR
authors.lastname: Simard
authors.forename: K
authors.initials: K
authors.lastname: Zerres
authors.forename: A H
authors.initials: AH
authors.lastname: Burghes
mesh_terms: D000483:Alleles; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005808:Genes, Recessive; D005819:Genetic Markers; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009136:Muscular Dystrophies / Q000145:classification / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013118:Spinal Cord Diseases / Q000145:classification / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D005819:Genetic Markers