A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy

Wu, X., Wang, S. H., Sun, J., Krainer, A. R., Hua, Y., Prior, T. W. (2017) A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. Hum Mol Genet. ISSN 0964-6906

URL: https://www.ncbi.nlm.nih.gov/pubmed/28460014
DOI: 10.1093/hmg/ddx166

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced expression of survival of motor neuron (SMN), a protein expressed in humans by two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences and a 5-nucleotide insertion in SMN2. SMA is subdivided into four main types, with type I being the most severe. SMN2 copy number is a key positive modifier of the disease, but it is not always inversely correlated with clinical severity. We previously reported the c.859G>C variant in SMN2 exon 7 as a positive modifier in several patients. We have now identified A-44G as an additional positive disease modifier, present in a group of patients carrying 3 SMN2 copies but displaying milder clinical phenotypes than other patients with the same SMN2 copy number. One of the three SMN2 copies appears to have been converted from SMN1, but except for the C6T transition, no other changes were detected. Analyzed with minigenes, SMN1C6T displayed a approximately 20% increase in exon 7 inclusion, compared to SMN2. Through systematic mutagenesis, we found that the improvement in exon 7 splicing is mainly attributable to the A-44G transition in intron 6. Using RNA-affinity chromatography and mass spectrometry, we further uncovered binding of the RNA-binding protein HuR to the -44 region, where it acts as a splicing repressor. The A-44G change markedly decreases the binding affinity of HuR, resulting in a moderate increase in exon 7 inclusion.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > introns
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > RNA binding protein
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing
diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: Matt Covey
Date Deposited: 05 May 2017 20:27
Last Modified: 05 May 2017 20:27
Related URLs:
URI: http://repository.cshl.edu/id/eprint/34706

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