A rare variant (c.863G>T) in exon 7 of SMN1 disrupts mRNA splicing and is responsible for spinal muscular atrophy

• Published in: European journal of human genetics : EJHG 2016-06, Vol.24 (6), p.864-870
• Main Authors: Qu, Yu-Jin, Bai, Jin-Li, Cao, Yan-Yan, Zhang, Wen-Hui, Wang, Hong, Jin, Yu-Wei, Song, Fang
• Format: Article
• Language: English
• Subjects: Binding Sites; Case-Control Studies; Cell survival; Cells, Cultured; Child; Clonal deletion; Exons; Female; Gene deletion; Genes; Genetics; Hereditary diseases; Heterogeneous Nuclear Ribonucleoprotein A1; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism; Humans; Infant, Newborn; Male; Mutation; Nerve Tissue Proteins - metabolism; Neuromuscular diseases; Paralysis; Patients; Pediatrics; Pneumonia; Protein Binding; Regulatory sequences; RNA Splicing; Serine-Arginine Splicing Factors - metabolism; SMN protein; Spinal Muscular Atrophies of Childhood - diagnosis; Spinal Muscular Atrophies of Childhood - genetics; Spinal muscular atrophy; Splicing factors; Survival of Motor Neuron 1 Protein - genetics; Survival of Motor Neuron 1 Protein - metabolism
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2015.213

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by deletion or mutation of SMN1 (survival motor neuron 1). SMN exon 7 splicing is regulated by a number of exonic and intronic regulatory sequences and the trans-factors that bind them. Variants located in or near these regulated regions should be evaluated to determine their effect on splicing. We identified the rare variant c.863G>T (r.835_*3del, p.Gly279Glufs*5) in exon 7 of SMN1 in three patients affected with type I or type II SMA. Most of the SMN1 transcripts exhibited complete loss of exon 7 in vivo. The ex vivo splicing assay demonstrated that the variant disrupts inclusion of exon 7 (~85%) in the SMN1 mRNA; replacement with various bases yielded a variety of splicing effects in SMN1 and SMN2 pre-mRNA. The c.863G>T (r.835_*3del, p.Gly279Glufs*5) variant is located in a region that includes binding sites for multiple splicing factors including Tra2β1. Thus, the variant disrupts Tra2β1 binding, but does not affect binding of hnRNP A1. These findings demonstrate how rare variants influence pre-mRNA splicing of SMN and reveal the functional influence of c.863G>T (r.835_*3del, p.Gly279Glufs*5) variant in patients with SMA.