title: Exclusion of Htra2-beta1, an up-regulator of full-length SMN2 transcript, as a modifying gene for spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by homozygous mutations of the survival motor neuron gene 1 (SMN1). In rare cases sibs with identical 5q13-homologs and identical SMN1 mutations can show variable phenotypes from unaffected to affected, suggesting the influence of modifying genes. SMN is part of an 800 kDa macromolecular complex that plays an essential role in snRNP biogenesis and pre-mRNA splicing. Due to a single nucleotide difference within SMN1 exon 7 that disrupts an exonic splicing enhancer (ESE), SMN2, a nearly identical copy of SMN1, predominantly expresses alternatively spliced transcripts lacking exon 7, whereas SMN1 mainly produces full-length transcripts. The SR-like trans-acting splicing factor Htra2-beta1 was shown to interact with this ESE and to restore full-length SMN2 expression in vivo in a concentration-dependent manner. Since Htra2-beta1 prevents skipping of exon 7 it is obvious to ask whether mutations within Htra2-beta1 are responsible for the intrafamilial variability of the SMA phenotype. We sequenced either RT-PCR products or genomic DNA covering the complete coding region of Htra2-beta1 as well as the putative promoter of 36 sibs belonging to 15 SMA families with discordant phenotypes but identical genotypes. Neither a mutation nor a polymorphism was found within Htra2-beta1. Additionally, we performed quantitative analysis of Htra2-beta isoforms from 26 sibs without identifying any significant difference between phenotypically discordant sibs. Based on these data, we suggest that the intrafamilial phenotypic variability in SMA families is not caused by polymorphic variants or transcription differences within Htra2-beta1.
authors.affiliation: Institute of Human Genetics, Bonn, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Helmken
authors.forename: B
authors.initials: B
authors.lastname: Wirth
mesh_terms: D014644:Genetic Variation; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C097083:TRA2B protein, human; D000068103:Serine-Arginine Splicing Factors