Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy
Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy
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中国脊髓性肌萎缩症运动神经元1存活突变谱及变异体功能分析。
DOI：
10.1016/j.jmoldx.2016.05.004
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发表时间：
2016-09-01
影响因子：
4.1
通讯作者：
Song, Fang
中科院分区：
文献类型：
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作者：
Qu, Yu-jin;Bai, Jin-li;Song, Fang
近端脊髓性肌萎缩症（SMA）是一种常见的致命性常染色体隐性遗传病，由运动神经元1 （SMN1）的缺失或突变引起。在这里，我们研究了653名中国SMA患者的分子病理学，发现大约88.2%的SMN1外显子7纯合子缺失，6.3%的SMN1外显子7杂合子缺失。通过克隆测序，在34例杂合子SMN1丢失患者中检测到SMN1变异。在其中的27例中，鉴定出15种变异：5种是未报道的新变异[c -7_9del(p。p. ser8lysfs *23, p. gln14 *, p. val19glyfs *21, p. leu228 *, p. tyr277cys), p. tyr109cys, p. ile249tyrfs *16, p. tyr272trpfs *35，和c.835- 5t>g]，其中5例以前仅在中国患者中发现（p. ser8lysfs *23, p. gln14 *, p. val19glyfs *21, p. tyr277cys），另有5例在其他人群中报道[p。Ala2Gly, p.Gln15*, p.Glu134Lys, p.Ser230Leu，和c.863G>T （r.835_*3del, p.Gly279Glufs*5）。变异p.Ser8Lysfs*23和p.Leu228*在中国SMA中最常见。5个变异（p.Ser8Lysfs*23、p.Gln14*、p.Gln15*、p.Val19Glyfs*21和p.Leu228*）导致过早终止密码子，可能导致SMN1 mRNA无义介导的衰变。新变异c -7_9del （p.0）导致翻译起始密码子（AUG）缺失，导致全长SMN蛋白丢失。新变异c.835-5T>G位于一个剪接位点，导致90%的外显子7跳变。我们的研究有助于对SMA患者的早期诊断，揭示了中国SMA患者中SMN1的特异性突变谱，以及中国和高加索患者之间观察到的细微变异的高度遗传异质性。
Proximal spinal muscular atrophy (SMA) is a common fatal autosomal recessive disorder caused by deletion or mutation of the survival of motor neuron 1 (SMN1). Here, we studied SMA molecular pathology in 653 Chinese patients and found approximately 88.2% with homozygous SMN1 exon 7 deletion and 6.3% with heterozygous exon 7 loss using multiplex ligation-dependent probe amplification. SMN1 variants were detected in 34 patients with heterozygous SMN1 loss by clone sequencing. In 27 of them, 15 variants were identified: five were unreported novel variants [c.-7_9del(p.0), p.Tyr109Cys, p.Ile249Tyrfs*16, p.Tyr272Trpfs*35, and c.835-5T>G], five were previously found only in Chinese patients (p.Ser8Lysfs*23, p.Gln14*, p.Val19Glyfs*21, p.Leu228*, and p.Tyr277Cys), and five were reported in other populations [p.Ala2Gly, p.Gln15*, p.Glu134Lys, p.Ser230Leu, and c.863G>T (r.835_*3del, p.Gly279Glufs*5)]. Variants p.Ser8Lysfs*23 and p.Leu228* were the most common in Chinese SMA. Five variants (p.Ser8Lysfs*23, p.Gln14*, p.Gln15*, p.Val19Glyfs*21, and p.Leu228*) resulted in premature stop codons, likely causing SMN1 mRNA nonsense-mediated decay. The novel variant c.-7_9del (p.0) caused deletion of the translation start codon (AUG), resulting in full-length SMN protein loss. The novel variant c.835-5T>G, located in a splice site, resulted in 90% exon 7 skipping. Our study could facilitate early diagnosis for SMA patients in mutation detection and revealed the specific mutation spectrum of SMN1 in Chinese SMA and high genetic heterogeneity in subtle variants observed between patients from China and Caucasians.