Molecular analysis of SMN1, SMN2, NAIP, GTF2H2, and H4F5 genes in 157 Chinese patients with spinal muscular atrophy

• Published in: Gene 2013-04, Vol.518 (2), p.325-329
• Main Authors: He, Jin, Zhang, Qi-Jie, Lin, Qi-Fang, Chen, Ya-Fang, Lin, Xiao-Zhen, Lin, Min-Ting, Murong, Shen-Xing, Wang, Ning, Chen, Wan-Jin
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Child; Child, Preschool; DNA Copy Number Variations; Female; Genetic Predisposition to Disease; Genotype; Genotype–phenotype analysis; Humans; Infant; Infant, Newborn; Male; Muscular Atrophy, Spinal - genetics; Mutation, Missense; Nerve Tissue Proteins - genetics; Neuronal Apoptosis-Inhibitory Protein - genetics; Phenotype; Quantification; Sequence Deletion; Spinal muscular atrophy; Subtle mutation; Survival motor neuron gene; Survival of Motor Neuron 1 Protein - genetics; Survival of Motor Neuron 2 Protein - genetics; Transcription Factor TFIIH - genetics; Transcription Factors - genetics; Young Adult
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2012.12.109

Spinal muscular atrophy (SMA) is a common and lethal autosomal recessive neurodegenerative disorder, which is caused by mutations of the survival motor neuron 1 (SMN1) gene. Additionally, the phenotype is modified by several genes nearby SMN1 in the 5q13 region. In this study, we analyzed mutations in SMN1 and quantified the modifying genes, including SMN2, NAIP, GTF2H2, and H4F5 by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), multiplex ligation-dependent probe amplification (MLPA), TA cloning, allele-specific long-range PCR, and Sanger sequencing in 157 SMA patients. Most SMA patients (94.90%) possessed a homozygous SMN1 deletion, while 10 patients demonstrated only the absence of exon 7, but the presence of exon 8. Two missense mutations (c.689 C>T and c.844 C>T) were identified in 2 patients who both carried a single copy of SMN1. We found inverse correlations between SMN2, the NAIP copy number, and the clinical severity of the disease. Furthermore, 7 severe type I patients possessed large-scale deletions, including SMN1, NAIP, and GTF2H2. We conclude that SMN1 gene conversion, SMN1 subtle mutations, SMN2 copy number, and the extent of deletion in the 5q13 region should all be considered in the genotype–phenotype analysis of SMA. ► SMN1 and modifying genes were analyzed simultaneously in 157 Chinese SMA patients. ► Two missense mutations were identified in 2 non SMN1-deleted patients. ► Severe type I patients with large-scale deletions were analyzed in detail. ► Variants of SMN1 and modifying genes should all be considered in the analysis of SMA.