Molecular Analysis and Prenatal Prediction of Spinal Muscular Atrophy in Chinese Patients by the Combination of Restriction Fragment Length Polymorphism Analysis, Denaturing High-Performance Liquid Chromatography, and Linkage Analysis

Chen, Wan-Jin; Wu, Zhi‐Ying; Lin, Min; Su, J; Lin, Yih‐Bin; Murong, Shen-Xing; Wang, Ning

doi:10.1001/archneur.64.2.225

Cited by 14 publications

(9 citation statements)

References 17 publications

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“…It was observed that the majority of patients with more SMN1 gene deletions resulted in a severe phenotype. Our results of exon 7 deletion were consistent with the studies from Taiwan, Hong Kong, and Fujian Province, China (Chang et al, 1995;Tsai et al, 2001;Wong and Chan, 2001;Su et al, 2005;Chen W.J. et al, 2007).…”

Section: Discussionsupporting

confidence: 92%

“…The genomic complexity of the SMN region and its high degree of variability hamper the ability to directly screen the SMA carriers. Thus the comprehensive SMA tests including SMA deletion analysis, linkage analysis, and SMA heterozygosity detection should be the most complete evaluation of the clinical diagnosis or suspicion of SMA (Chan et al, 2004;Dastur et al, 2006;Chen W.J. et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…The finding of homozygous deletions of exon 7 and/or exon 8 of SMN1 patients with consistent clinical features is generally considered to be diagnostic of SMA Chang et al, 1995;Chen K.L. et al, 1999;Chen W.J. et al, 2007;Tsai et al, 2001;Su et al, 2005;Watihayati et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Deletion analysis of SMN1 and NAIP genes in southern Chinese children with spinal muscular atrophy

Liang

Chen

et al. 2009

J. Zhejiang Univ. Sci. B

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Spinal muscular atrophy (SMA) is a disorder characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk paralysis as well as muscular atrophy. Three types of SMA are recognized depending on the age of onset, the maximum muscular activity achieved, and survivorship: SMA1, SMA2, and SMA3. The survival of motor neuron (SMN) gene has been identified as an SMA determining gene, whereas the neuronal apoptosis inhibitory protein (NAIP) gene is considered to be a modifying factor of the severity of SMA. The main objective of this study was to analyze the deletion of SMN1 and NAIP genes in southern Chinese children with SMA. Here, polymerase chain reaction (PCR) combined with restriction fragment length polymorphism (RFLP) was performed to detect the deletion of both exon 7 and exon 8 of SMN1 and exon 5 of NAIP in 62 southern Chinese children with strongly suspected clinical symptoms of SMA. All the 32 SMA1 patients and 76% (13/17) of SMA2 patients showed homozygous deletions for exon 7 and exon 8, and all the 13 SMA3 patients showed single deletion of SMN1 exon 7 along with 24% (4/17) of SMA2 patients. Eleven out of 32 (34%) SMA1 patients showed NAIP deletion, and none of SMA2 and SMA3 patients was found to have NAIP deletion. The findings of homozygous deletions of exon 7 and/or exon 8 of SMN1 gene confirmed the diagnosis of SMA, and suggested that the deletion of SMN1 exon 7 is a major cause of SMA in southern Chinese children, and that the NAIP gene may be a modifying factor for disease severity of SMA1. The molecular diagnosis system based on PCR-RFLP analysis can conveniently be applied in the clinical testing, genetic counseling, prenatal diagnosis and preimplantation genetic diagnosis of SMA.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Deletion analysis of SMN1 and NAIP genes in southern Chinese children with spinal muscular atrophy

Liang

Chen

et al. 2009

J. Zhejiang Univ. Sci. B

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“…PCR-RFLP was applied for screening the homozygous deletion of SMN gene as our previous report [35]. In brief, the exon 7/8 and flanking areas of the SMN1 and SMN2 genes were amplified by PCR with the primers of exon 7 (forward 5′-AGACTATCAACTTAATTTCTGATCA-3′, reverse 5′-CCTTCCTTCTTTTTGATTTTGTTT-3′) and exon 8 (forward 5′-TAATAACCAAATGCAATGTGAA-3′, reverse 5′-CTACAACACCCTTCTCACAG-3′).…”

Section: Methodsmentioning

confidence: 99%

Modeling the differential phenotypes of spinal muscular atrophy with high-yield generation of motor neurons from human induced pluripotent stem cells

Lin

Qian

et al. 2017

Oncotarget

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Spinal muscular atrophy (SMA) is a devastating motor neuron disease caused by mutations of the survival motor neuron 1 (SMN1) gene. SMN2, a paralogous gene to SMN1, can partially compensate for the loss of SMN1. On the basis of age at onset, highest motor function and SMN2 copy numbers, childhood-onset SMA can be divided into three types (SMA I-III). An inverse correlation was observed between SMN2 copies and the differential phenotypes of SMA. Interestingly, this correlation is not always absolute. Using SMA induced pluripotent stem cells (iPSCs), we found that the SMN was significantly decreased in both SMA III and SMA I iPSCs derived postmitotic motor neurons (pMNs) and γ-aminobutyric acid (GABA) neurons. Moreover, the significant differences of SMN expression level between SMA III (3 copies of SMN2) and SMA I (2 copies of SMN2) were observed only in pMNs culture, but not in GABA neurons or iPSCs. From these findings, we further discovered that the neurite outgrowth was suppressed in both SMA III and SMA I derived MNs. Meanwhile, the significant difference of neurite outgrowth between SMA III and SMA I group was also found in long-term cultures. However, significant hyperexcitability was showed only in SMA I derived mature MNs, but not in SMA III group. Above all, we propose that SMN protein is a major factor of phenotypic modifier. Our data may provide a new insight into recognition for differential phenotypes of SMA disease.

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“…20,22,23 We also assessed the genotype contribution of SMA carriers in the Chinese population by comparative genotyping of newborn samples and SMA core families. In addition, during the analysis of SMA patients, we found a novel SMN1 splice-site mutation at the junction between intron 6 and exon 7 (c.835-1G4A).…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population

Sheng-Yuan

Xiong

Chen³

et al. 2010

Eur J Hum Genet

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Screening for carriers of spinal muscular atrophy (SMA) is necessary for effective clinical/prenatal diagnosis and genetic counseling. However, a population-based study of SMA prevalence in mainland China has not yet been conducted. In this study, the copy number of survival motor neuron (SMN) genes was determined in 1712 newborn cord blood samples collected from southern China and from 25 core families, which included 26 SMA patients and 44 parents, to identify SMA carriers. The results presented 13 groups with different SMN1/SMN2 ratios among 1712 newborn individuals, which corresponded to 1535 subjects with two copies of SMN1, 119 with three copies of SMN1, 17 with four copies of SMN1, and 41 with a heterozygous deletion of SMN1 exon 7. Simultaneously, two '2+0' genotypes and two point mutations were found among the 44 obligate carriers in the core families, including a novel SMN1 splice-site mutation that was identified in the junction between intron 6 and exon 7 (c. 835-1G4A). These results indicated that the carrier frequency is 1/42 in the general Chinese population and that duplicated SMN1 alleles and de novo deletion mutations are present in a small number of SMA carriers. In addition, we developed and validated a new alternative screening method using a reverse dot blot assay for rapid genotyping of deletional SMA. Our research elucidated the genetic load and SMN gene variants that are present in the Chinese population, and could serve as the basis for a nationwide program of genetic counseling and clinical/prenatal diagnosis to prevent SMA in China.

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Molecular Analysis and Prenatal Prediction of Spinal Muscular Atrophy in Chinese Patients by the Combination of Restriction Fragment Length Polymorphism Analysis, Denaturing High-Performance Liquid Chromatography, and Linkage Analysis

Cited by 14 publications

References 17 publications

Deletion analysis of SMN1 and NAIP genes in southern Chinese children with spinal muscular atrophy

Deletion analysis of SMN1 and NAIP genes in southern Chinese children with spinal muscular atrophy

Modeling the differential phenotypes of spinal muscular atrophy with high-yield generation of motor neurons from human induced pluripotent stem cells

Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population

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