Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy

Hum Mutat. 2005 Jan;25(1):64-71. doi: 10.1002/humu.20111.


The autosomal recessive spinal muscular atrophy (SMA), a neuromuscular disease and frequent cause of early death in childhood, is caused in 96% of patients by homozygous absence of the survival motor neuron gene (SMN1). The severity of the disease is mainly determined by the copy number of SMN2, a copy gene which predominantly produces exon 7-skipped transcripts and only low amount of full-length transcripts that encode for a protein identical to SMN1. Only about 4% of SMA patients bear one SMN1 copy with an intragenic mutation. A comprehensive molecular genetic analysis of 34 SMA patients who carry one SMN1 gene is presented, including 18 that were previously published. Haplotype analysis with the microsatellite markers Ag1-CA and C212 in these SMA families turned out to be a reliable accessory method in predicting known SMN1 mutations in SMA patients carrying one SMN1 copy. Five novel missense mutations were identified that are localized in: exon 2a c.88G>A (p.D30N) and c.131A>T (p.D44V); exon 3 c.283G>C (p.G95R) and c.332C>G (p.A111G); and exon 6 c.784A>G (p.S262G), respectively. The survival motor neuron (SMN) protein has been shown to be a component of a large complex (termed the SMN complex) that promotes the formation of spliceosomal U small nuclear ribonucleoproteins (snRNPs). Within this complex, SMN forms oligomers and directly interacts via its N-terminus with SMN-interacting protein 1 (SIP1) and via its central Tudor domain with spliceosomal (Sm) proteins. We performed in vitro interaction studies to test whether SMA-causing missense mutations identified in this study interfere with the reported interactions of SMN. Our results show that mutations p.G95R and p.A111G reduce SMN binding to Sm proteins, further confirming the previous finding that the Tudor domain is the essential binding site of SMN to Sm-proteins. However, all mutations, including those in exon 2a, a region shown to be important for the binding of SMN to SIP1, do not disturb the interaction of SMN to SIP1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autoantigens / metabolism
  • Cell Line
  • Cells, Cultured
  • Child, Preschool
  • Chromosomes, Human, Pair 5
  • Cyclic AMP Response Element-Binding Protein / genetics*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA Mutational Analysis
  • Exons
  • Female
  • Gene Dosage
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Muscular Atrophy, Spinal / genetics*
  • Mutation*
  • Mutation, Missense
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Pedigree
  • Protein Binding
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Ribonucleoproteins, Small Nuclear / metabolism
  • SMN Complex Proteins
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • snRNP Core Proteins


  • Autoantigens
  • Cyclic AMP Response Element-Binding Protein
  • GEMIN2 protein, human
  • Nerve Tissue Proteins
  • RNA-Binding Proteins
  • Recombinant Fusion Proteins
  • Ribonucleoproteins, Small Nuclear
  • SMN Complex Proteins
  • SMN1 protein, human
  • SMN2 protein, human
  • SNRPN protein, human
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • snRNP Core Proteins

Associated data

  • GENBANK/U18423
  • OMIM/253300
  • OMIM/253400
  • OMIM/253550
  • OMIM/600354
  • OMIM/601627
  • RefSeq/NM_022875