Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene
Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene
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DOI：
10.1007/s00439-008-0598-1
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发表时间：
2009-02-01
期刊：
影响因子：
5.3
通讯作者：
Tizzano, Eduardo F.
中科院分区：
文献类型：
--
作者：
Alias, Laura;Bernal, Sara;Tizzano, Eduardo F.
脊柱肌肉萎缩（SMA）是由SMN1基因突变引起的。我们使用PCR-RFLP，SMN基因剂量分析，链接研究，远程PCR和直接测序研究了745例西班牙患者中SMA的分子病理。我们的系统方法使我们能够完成736名SMA患者（98.8％）的基因测试和风险评估。女性更频繁地受到疾病的急性形式（I型）的影响，而慢性形式（II-III型）占男性（p <0.008）。在671例患者中检测到SMN1基因的缺乏（90％），在37例（5％）中观察到混合SMN1-SMN2基因。此外，我们在28例患者中检测到13个小突变（3.8％），其中4例以前在其他人群（C.91DIPT; C.770_780DUP11; P.TYR272CYS and P.THR274ILE）中发现，而迄今仅发现5个突变。在西班牙患者中（c.399_402delagag，p.ile116phe，p.gln136glu， C.740DUPC和C.834+2T> g）。 C.399_402Delagag突变占所有西班牙SMA患者的1.9％。最后，我们发现了四个新型突变：c.312dupa，c.411delt，p.trp190x和p.met263thr。我们的结果证实，大多数SMA病例是由于SMA基因座的重复区域中遗传重排引起的，导致SMN1基因缺乏功能。相比之下，祖先遗传的小突变仅造成少量病例。外显子3和6（c.399_402delagag; c.770_780dup11; p.tyr272cys; p.Thr274ile）的四次普遍变化占我们这些细微突变的患者的70％。提出了一种具有紧密疏水芳香相互作用的SMN-SMN二聚体模型，以解释蛋白质C末端突变的影响。
Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene. We have studied the molecular pathology of SMA in 745 unrelated Spanish patients using PCR-RFLP, SMN gene dosage analysis, linkage studies, long-range PCR and direct sequencing. Our systematic approach allowed us to complete genetic testing and risk assessment in 736 SMA patients (98.8%). Females were more frequently affected by the acute form of the disease (type I), whereas chronic forms (type II-III) predominated in males (p < 0.008). Absence of the SMN1 gene was detected in 671 patients (90%), and hybrid SMN1-SMN2 genes were observed in 37 cases (5%). Furthermore, we detected 13 small mutations in 28 patients (3.8%), four of which were previously identified in other populations (c.91dupT; c.770_780dup11; p.Tyr272Cys and p.Thr274Ile), while five mutations were found to date only in Spanish patients (c.399_402delAGAG, p.Ile116Phe, p.Gln136Glu, c.740dupC and c.834+2T > G). The c.399_402delAGAG mutation accounted for 1.9% of all Spanish SMA patients. Finally, we discovered four novel mutations: c.312dupA, c.411delT, p.Trp190X and p.Met263Thr. Our results confirm that most SMA cases are due to large genetic rearrangements in the repetitive region of the SMA locus, resulting in absence-dysfunction of the SMN1 gene. By contrast, ancestrally inherited small mutations are responsible for only a small number of cases. Four prevalent changes in exons 3 and 6 (c.399_402delAGAG; c.770_780dup11; p.Tyr272Cys; p.Thr274Ile) accounted for almost 70% of our patients with these subtle mutations. An SMN-SMN dimer model featuring tight hydrophobic-aromatic interactions is proposed to explain the impact of mutations at the C-terminal end of the protein.