G.P.231: A novel splice-site mutation in SMN1 resulting in a very severe SMA1 phenotype

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive genetic motor neuron disorder caused by a defect in the survival motor neuron 1 (SMN1) gene resulting from deletions or other mutations. The number of copies of SMN2, a gene paralogous to SMN1, modifies clinical course. The homozygous deletion of exon 7 is the most recurrent molecular defect but heterozygous deletions in compound with single nucleotide intragenic mutations have also been reported. We describe the clinical and molecular features of a child born to not consanguineous parents who developed a severe muscle hypotonia at 10 days of age. Clinical diagnosis was compatible with SMA type I (Werdnig–Hoffmann) phenotype. SMA locus genotype by quantitative PCR analysis revealed one copy of both SMN1 and SMN2 genes. Sequence analysis in the proband disclosed the heterozygous novel c.888+1G>C substitution affecting the donor splice site between exon 7 and intron 7. The deletion and the point mutation are independently inherited from the parents. Standard and quantitative RT-PCR experiments on proband’s cDNA disclosed a severe reduction of the full-length/delta7 ratio of SMN isoforms as well as the presence of a transcript originating from SMN1 but lacking exon 7. Approximately 3–5% of patients with SMA retain at least one copy of the SMN1 gene carrying pathogenic insertions, deletions, or point mutations on the other allele. The number of intragenic mutations affecting splicing is even narrower. Our findings demonstrate that the novel c.888+1G>C mutation is highly deleterious, resulting in the almost total exclusion of exon 7. Sequence analysis is helpful to identify these defects whose effects might be highly detrimental on SMN stability and function.