title: Compound heterozygous mutation in two unrelated cases of Chinese spinal muscular atrophy patients.
abstract: BACKGROUND
  Infantile proximal spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder. Approximately 90% - 95% cases of SMA result from homozygous deletion of survival motor neuron gene 1 (SMN1) and 5% cases are caused by compound heterozygous mutation (a SMN1 deletion on one allele and a subtle mutation on the other allele).
  
  
  METHODS
  In this research, two unrelated patients were clinically diagnosed according to the criteria of proximal SMA. Genetic diagnosis was performed to detect the homozygous deletion of exon 7 of SMN1 by PCR-restriction fragment length polymorphism (RFLP) and genomic sequencing. Multiplex ligation-dependent probe amplification (MLPA) analysis was carried out to measure copy numbers of SMN1, SMN2 and neuronal apoptosis inhibitor protein (NAIP) in the patients. Further sequencing of SMN1 allele-specific PCR (AS-PCR) and SMN1 clones were also performed to analyze the point mutation of SMN1 gene. Additionally, the pedigree analysis of these two families was carried out to identify the transmission of the mutation.
  
  
  RESULTS
  The inconsistent results using PCR-RFLP and genomic sequencing showed homozygous deletion of exon 7 of SMN1 and heterozygous deletion accompanied with a suspicious mutation in SMN1 gene, respectively. MLPA analysis of these two cases exhibited one SMN1 copy deletion. One identical c.863G > T (p.Arg288Met) mutation was found in two cases by sequencing the SMN1 clones, which confirmed that both cases were SMA compound heterozygotes. One case showed partial conversion to form hybrid SMN (SMN2 I7/SMN1 E8) identified by clones sequencing and another case carrying 3 SMN2 implied complete conversion from SMN1 to SMN2.
  
  
  CONCLUSIONS
  p.Arg288Met is more a disease-causing mutation than a polymorphism variation, and children with this mutation may have more severe phenotypes.
authors.affiliation: Department of Medical Genetics, Capital Institute of Pediatrics, Beijing 100020, China.
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Qu
authors.forename: Fang
authors.initials: F
authors.lastname: Song
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Yang
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Jin
authors.forename: Jin-Li
authors.initials: JL
authors.lastname: Bai
mesh_terms: D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009154:Mutation; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000235:genetics; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: D051616:Neuronal Apoptosis-Inhibitory Protein; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein