Different molecular basis for spinal muscular atrophy in South African black patients

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disorder occurring at a rate of between 1/5,000 and 1/10,000 births in most European countries. The phenotype results from the degeneration of the anterior horn cells of the spinal cord, resulting in symmetrical muscle weakness and wasting. The disorder can be classified according to the severity of the disease and the age of onset into three major types. Two candidate SMA genes, NAIP and SMN, isolated from the 5q13 region, have been reported to be homozygously deleted in approximately 30% and >95% of SMA patients, respectively. Black SMA patients have been reported to have facial muscle weakness more commonly. This study aimed to determine the molecular basis of SMA in South African black SMA patients. The SMN gene was found to be homozygously deleted in 65.5% (19/29) of patients, significantly less frequently than in previous studies. Similarly, the NAIP gene was homozygously deleted in a smaller number, 14% (4/29) of patients; 47% (9/19) of SMN deletion patients appeared to have deletions of telomeric exon 7, but not exon 8. In at least six of these patients a gene conversion event has occurred. No detectable deletions were found in 35% (10/29) of patients. Haplotype analysis in the nondeletion patients, using six closely linked markers, provided no evidence for a founder mutation. No mutations were found in exons 3 and intron 6 through exon 8 by sequence analysis of these nondeletion patients. It is proposed that the differences in the SMA phenotype observed in black patients may in part be explained by a different molecular basis.

Study of Survival of Motor Neuron (SMN) and Neuronal Apoptosis Inhibitory Protein (NAIP) gene deletions in SMA patients

“…This may be one of the reasons for discrepancy in the deletion frequency in our patients group. The other reason for the difference in the frequency may be the population variation as in South African black patients 65 % [21] had deletion, Saudi Arabian patients had 72 % deletion [22], Polish had 63 % [23] and Vietnamese showed 41 % [24] deletion, while many other studies showed more than 90 % of deletion in SMN1 gene. We have observed that 2 of our type II patients and 1 of type III patient had deletion of exon 7 only but retaining exon 8 of SMN1 gene, this may be due to a gene conversion event at this locus.…”

Spinal muscular atrophy: molecular genetics and diagnostics

“…The frequency of small intragenic SMN1 mutations and/or of SMA unlinked to chromosome 5q13 may be higher in certain non-European populations, such as black South African patients [53], although data that do not support this hypothesis also exist [54].…”

An ~140-kb deletion associated with feline spinal muscular atrophy implies an essentialLIX1function for motor neuron survival

“…While no mutational variant was found in exons or splice-site consensus sequences, we cannot conclusively exclude a LIX1 expression defect in these or other non-SMN1 SMA patients until LIX1-expressing tissue can be interrogated. Furthermore, populations other than that represented by our predominantly Caucasian patient sample may have higher prevalence of SMA caused by mutations at other loci or undetected SMN1 mutations (Stevens et al 1999). …”