A frame–shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients

Abstract

Spinal muscular atrophy (SMA) is a frequent autosomal recessive disease characterized by degeneration of the motor neurons of the spinal cord causing proximal paralysis with muscle atrophy. The region on chromosome 5q13 encompassing the disease gene is particularly unstable and prone to large-scale deletions whose characterization recently led to the identification of the survival motor neuron (SMN) gene. We now present a genetic analysis of 54 unrelated Spanish SMA families that has revealed a 4-basepair (bp) deletion (AGAG) in exon 3 of SMN in four unrelated patients. This deletion, which results in a frameshift and a premature stop codon, occurs on the same haplotype background, suggesting that a single mutational event is involved in the four families. The other patients showed either deletions of the SMN gene (49/54) or a gene conversion event changing SMN exon 7 into its highly homologous copy (cBCD541, 1/54). This observation gives strong support to the view that mutations of the SMN gene are responsible for the SMA phenotype as it is the first frameshift mutation reported in SMA.

The proportion of mutations predicted to have a deleterious effect differs between gain and loss of function genes in neurodegenerative disease

“…Other genes responsible for neurodegenerative disorders have a clear loss of function role, most notably SMN1 (MIM# 600354) where gene deletions cause spinal muscular atrophy (SMA) (Bussaglia, et al, 1995). Point mutations in this gene thus are expected to also abrogate the function of the protein as is the case for mutations in the parkin gene (PARK2; MIM# 602544) that lead to a recessive form of Parkinson Disease (PD) (Kitada, et al, 1998).…”

SMN protein analysis in fibroblast, amniocyte and CVS cultures from spinal muscular atrophy patients and its relevance for diagnosis

“…[6][7][8][9][10][11][12] Several missense or frameshift mutations in SMNt have also been reported providing further evidence that SMNt is responsible for SMA. 6,[13][14][15][16][17] SMNt differs from SMNc at only two nucleotides in the coding region in exons 7 and 8, respectively, which do not alter the amminoacid sequence. 6 However, the two genes generate different proportions of alternatively spliced isoforms: about 90% of transcripts from the SMNt gene are full length, whilst the SMNc gene produces predominantly transcripts which lack exon 7 and, to a less amount, transcripts that lack exon 5 or both exons 5 and 7 as well as full length transcripts.…”

Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability

“…It has been associated with a large spectrum of phenotypes, from severe type I to non-symptomatic patients. [3][4][5] The SMN1 gene contains a C nucleotide at position six of exon 7 (Ex7+6) and produces predominantly full-length transcripts (FL-SMN). The SMN2 gene, however, contains a T nucleotide at this position, leading to a differentially spliced form that lacks exon 7 (D7-SMN).…”