Molecular Analysis of the SMN and NAIP Genes in Spanish Spinal Muscular Atrophy (SMA) Families and Correlation between Number of Copies of^cBCD541 and SMA Phenotype

Abstract

Spinal muscular atrophy is an autosomal recessive disorder which affects about 1 in 10,000 individuals. The three clinical forms of SMA were mapped to the 5q13 region. Three candidate genes have been isolated and shown to be deleted in SMA patients: the Survival Motor Neuron gene (SMN), the Neuronal Apoptosis Inhibitory Protein gene (NAIP) and the XS2G3 cDNA. In this report we present the molecular analysis of the SMN exons 7 and 8 and NAIP exon 5 in 65 Spanish SMA families. NAIP was mostly deleted in type I patients (67.9%) and SMN was deleted in 92.3% of patients with severe and milder forms. Most patients who lacked the NAIP gene also lacked the SMN gene, but we identified one type II patient deleted for NAIP exon 5 but not for SMN exons 7 and 8. Two other patients carried deletions of NAIP exon 5 and SMN exon 7 but retained the SMN exon 8. Three polymorphic variants from the SMN gene, showing changes on the sequence of the centromeric (cBCD541) and telomeric copies of the SMN gene, were found. In addition, we show several genetic rearrangements of the telomeric SMN gene, which include duplication of this gene in one normal chromosome, and putative gene conversion events in affected and normal chromosomes. Altogether these results corroborate the high genetic variability of the SMA region. Finally, we have determined the ratio between the number of centromeric and telomeric copies of the SMN gene in parents of SMA patients, showing that the majority of parents of types II and III patients carried three or more copies of the cBCD541 gene; we suggest a relationship between the number of copies of cBCD541 and the disease phenotype.

Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos

“…Its forced expression in vitro has been shown to suppress apoptosis in nonneuronal mammalian cells (15). NAIP exon 5 is deleted in 60% of type I SMA patients; in milder forms of the disease, deletions are identified only in 18% of affected individuals (11,(16)(17)(18). This gene is also deleted in 3% of normal carriers (11,17), arguing that it is not essential for motor neuron survival or that its function can be compensated by other genes, in particular the truncated centromeric copy.…”

“…In contrast, 95% of SMA patients have deletions of the telomeric SMN gene regardless of phenotype severity (10,(16)(17)(18)(19)(20). This has led to the assumption that the SMN gene is the more likely candidate whose dysfunction is responsible for the disease (16)(17)(18).…”

“…This has led to the assumption that the SMN gene is the more likely candidate whose dysfunction is responsible for the disease (16)(17)(18). The two copies on chromosome 5q13, telomeric SMN copy (SMN tel ) and centromeric SMN copy (SMN centr ), differ only in five nucleotides in their coding regions, none of which causes an amino acid change.…”

“…The two copies on chromosome 5q13, telomeric SMN copy (SMN tel ) and centromeric SMN copy (SMN centr ), differ only in five nucleotides in their coding regions, none of which causes an amino acid change. Rarely, asymptomatic carriers also show homozygous deletion of SMN tel (16,17,20,21). SMN centr is deleted in 2-3% of normal carriers (10,(17)(18)(19).…”

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

“…Deletions, most often associated with type I SMA, result in a drastic reduction in SMN protein [Lefebvre et al, 1995;Coovert et al, 1997]. Patients with Type II-IV SMA can have SMN2-like genes at the SMN1 locus and thus often possess three or four copies of SMN2 genes [Hahnen et al, 1996;van der Steege et al, 1996;Velasco et al, 1996;Burghes, 1997;DiDonato et al, 1997] capable of contributing variable amounts of functional and semi-functional SMN complexes [Lefebvre et al, 1995;Coovert et al, 1997;Burghes and Beattie, 2009] and modify disease presentation. Not surprisingly, disease severity correlates with SMN2 gene copy number, although this correlation is not absolute [Burghes, 1997;Vitali et al, 1999;Feldkotter et al, 2002;Tiziano et al, 2007].…”