An essential SMN interacting protein (SIP1) is not involved in the phenotypic variability of spinal muscular atrophy (SMA)

Abstract

The survival motor neuron (SMN) protein and the SMN interacting protein 1 (SIP1) are part of a 300 kD protein complex with a crucial role in snRNP biogenesis and pre-mRNA splicing. Both proteins are colocalised in nuclear structures called gems and in the cytoplasm. Approximately 96% of patients with autosomal recessive spinal muscular atrophy (SMA) show mutations in the SMN1 gene, while about 4% fail to show any mutation, despite a typical SMA phenotype. Additionally, sibs with identical 5q13 homologs and homozygous absence of SMN1 can show variable phenotypes which suggest that SMA is modified by other, yet unknown factors. Since both genes, SMN1 and SIP1, belong to the same pathway and are part of the same protein complex, it is obvious to ask whether mutations within SIP1 are responsible for both the phenotypic variability and the appearance of non-SMN mutated SMA patients. First, we identified the chromosomal location of SIP1 and assigned it to chromosomal region 14q13-q21 by fluorescence in situ hybridisation. No SMA related disorder has yet been assigned to this chromosomal region. Next, we determined the exon-intron structure of the SIP1 gene which encompasses 10 exons and identified five transcription isoforms. We sequenced either RT-PCR products or genomic DNA covering the complete coding region from 23 typical SMA patients who had failed to show any SMN1 mutation. No mutation and no polymorphism was found within SIP1. Additionally, we sequenced RT-PCR products or genomic fragments of the entire SIP1 coding region from 26 sibs of 11 SMA families with identical genotypes (∆7SMN/∆7SMN or ∆7SMN/other mutation) but different phenotypes and again no mutation was found. Finally, we performed quantitative analysis of RT-PCR products from the same 26 sibs. No difference in expression level of the five isoforms among phenotypically variable sibs was observed. Based on these data, we suggest that neither the phenotypic variability nor the 5q-unlinked SMA are caused by mutations within SIP1.

Gene targeting of Gemin2 in mice reveals a correlation between defects in the biogenesis of U snRNPs and motoneuron cell death

“…Although patients within families exhibited identical alterations in the SMN gene, they showed variations in disease phenotype indicative of other disease modifying genes. Thus, it was concluded that Gemin2 mutations are rare and they do not function as a disease modifier in SMA (29). However, this study did not address the point whether levels of Gemin2 protein are altered in these patients by mechanisms such as, for example, reduced levels of SMN protein (30).…”

Spinal muscular atrophy: molecular genetics and diagnostics

“…However, homozygous deletions of NAIP may simply reflect larger chromosomal deletions involving both SMN1 and SMN2. Likewise, phenotypic variations between siblings with identical 5q13 haplotypes did not correlate with mutations or differences in expression of Gemin2 (SIP1) [68]. H4F5 (SERF1) is closer to SMN1 on chromosome 5 than any other known gene.…”

Caenorhabditis elegans in the study of SMN-interacting proteins: a role for SMI-1, an orthologue of human Gemin2 and the identification of novel components of the SMN complex

“…Low levels of SMN result in the SMA phenotype, but alterations in the splicing of Gemin2 mRNA may also be involved in the disease pathogenesis of SMA (Aerbajinai et al 2002;Helmken et al 2000). Recently, a potential C. elegans homologue of the Gemin2 gene has been predicted, (The C. elegans Sequencing Consortium 1998).…”