title: 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 (delta7SMN/delta7SMN or delta7SMN/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.
authors.affiliation: Institute of Human Genetics, Bonn, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Helmken
authors.forename: A
authors.initials: A
authors.lastname: Wetter
authors.forename: S
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.forename: T
authors.initials: T
authors.lastname: Liehr
authors.forename: K
authors.initials: K
authors.lastname: Zerres
authors.forename: B
authors.initials: B
authors.lastname: Wirth
mesh_terms: D017398:Alternative Splicing; D002675:Child, Preschool; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D004247:DNA / Q000032:analysis / Q000097:blood; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007438:Introns; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics* / Q000473:pathology
chemical_list: D017931:DNA Primers; C108381:GEMIN2 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D004247:DNA