Abstract
BackgroundSpinal muscular atrophy (SMA) is mostly caused by homozygous deletions in the survival motor neuron 1 (SMN1) gene. SMN2, its paralogous gene, is a genetic modifier of the disease phenotype, and its copy number is correlated with SMA severity. The purpose of the study was to investigate the number of copies of the SMN1 and SMN2 genes in a Venezuelan population control sample and in patients with a presumptive diagnosis of SMA, besides estimating the frequency of mutation carriers in the population.ResultsSMN1 and SMN2 gene copies were assessed in 49 Venezuelan dweller unrelated normal individuals and in 94 subjects from 29 families with a SMA presumptive diagnosis, using the quantitative PCR method. A SMN1 deletion carrier frequency of 0.01 and 0.163 of homozygous absence of the SMN2 gene were found in the Venezuelan control sample. Deletion of SMN1 exon 7 was confirmed in 15 families; the remaining 14 index cases had two SMN1 copies and a heterogeneous phenotype not attributable to SMN deletions. Based on clinical features of the index cases and the SMN2 copy number, a positive phenotype-genotype correlation was demonstrated. No disease geographical aggregation was found in the country.ConclusionThe frequency of carriers of the deletion of exon 7 in SMN1 in the Venezuelan control population was similar to that observed in populations worldwide, while the frequency of 0 copies of the SMN2 gene (16.3 %) seems to be relatively high. All these findings have pertinent implications for the diagnosis and genetic counseling on SMA in Venezuela.
Highlights
Spinal muscular atrophy (SMA) is mostly caused by homozygous deletions in the survival motor neuron 1 (SMN1) gene
Homozygous deletion of the entire SMN1 gene or loss of its exon 7 causes spinal muscular atrophy (SMA, OMIM #253300), a recessive inherited neuromuscular disease characterized by muscle weakness and atrophy due to the progressive degeneration and loss of the motor
Quantitative analysis The results obtained according to the quantitative analyses showed that the ranges of 2−ΔΔCT values did not overlap with those corresponding to each category of gene copy numbers
Summary
Spinal muscular atrophy (SMA) is mostly caused by homozygous deletions in the survival motor neuron 1 (SMN1) gene. Normal individuals have two genes encoding SMN protein that are arranged in tandem on each chromosome: SMN1 (telomeric copy) and SMN2 (centromeric copy). Both genes share more than 99% nucleotide identity, differing only by five nucleotides. Homozygous deletion of the entire SMN1 gene or loss of its exon 7 causes spinal muscular atrophy (SMA, OMIM #253300), a recessive inherited neuromuscular disease characterized by muscle weakness and atrophy due to the progressive degeneration and loss of the motor Both genes produce equal transcript amounts, a large proportion of SMN2 transcripts lack exon 7, due to the c.840 C>T nucleotide transition (rs1164325688) in exon 7 which causes its skipping, resulting in a truncated, less stable, and poorly functional protein.
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