title: Subtle mutation detection of SMN1 gene in Chinese spinal muscular atrophy patients: implication of molecular diagnostic procedure for SMN1 gene mutations.
abstract: Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. Approximately 90-95% of SMA patients have a homozygous deletion of SMN1, and 5-10% of patients are believed to have subtle mutations. The molecular diagnosis of SMN1 subtle mutations is hampered by a highly homologous SMN2 gene. It is important to establish a rational molecular diagnostic procedure for SMN1 subtle mutations. We analyzed the SMN1 mutations in nine nonhomozygous patients by the following procedures: multiplex ligation-dependent probe amplification, genomic sequencing, T-A cloning on cDNA or genomic level, and/or real-time quantitative analysis. By the above molecular diagnostic procedure, six SMN1 subtle mutations, including c.5C>G(p.Ala2Gly), c.22_23 insA (p.Ser8LysfsX23), c.40G>T(p.Glu14X), c.43C>T(p.Gln15X), c.683T>A(p.Leu228X), and c.56delT(p.Val19GlyfsX21), were identified in nine Chinese patients. p.Glu14X has not been reported previously. Compared with the level of full-length SMN1 transcripts in the healthy carriers (14.1±4.5), the patient with p.Ala2Gly had no significant reduction (13.9±3.64, p=0.955). However, the levels in the patients carrying other mutations were significantly reduced (0.27±0.139 to 13.9±3.64, p=0.000-0.004). We present a reliable and rational diagnostic procedure for SMN1 subtle mutations, which would be helpful in molecular diagnosis of SMA compound heterozygotes. Our work extends the SMN1 mutation spectrum.
authors.affiliation: 1 Department of Medical Genetics, Capital Institute of Pediatrics , Beijing, China .
authors.forename: Jin-Li
authors.initials: JL
authors.lastname: Bai
authors.forename: Yu-Jin
authors.initials: YJ
authors.lastname: Qu
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Cao
authors.forename: Ee-Zhen
authors.initials: EZ
authors.lastname: Li
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Zhu
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Zhang
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Jin
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Song
mesh_terms: D019943:Amino Acid Substitution; D044466:Asian People; D002681:China; D005260:Female; D020271:Heredodegenerative Disorders, Nervous System / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D057089:Pathology, Molecular / Q000379:methods*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein