Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland
Dominant GDAP1 founder mutation is a common cause of axonal Charcot-Marie-Tooth disease in Finland
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DOI：
10.1007/s10048-013-0358-9
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发表时间：
2013-05-01
期刊：
影响因子：
2.2
通讯作者：
Tyynismaa, Henna
中科院分区：
文献类型：
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作者：
Auranen, Mari;Ylikallio, Emil;Tyynismaa, Henna
我们描述了一个创始人突变基因编码神经节苷脂诱导分化相关蛋白1（GDAP 1），导致氨基酸的变化p.H123R，作为常染色体显性轴突Charcot-Marie-Tooth（CMT 2）神经病在芬兰的常见原因。这种突变解释了芬兰高达14%的CMT 2，在芬兰，大多数轴突神经病患者仍然没有分子诊断。在28个家庭中，只有3个家庭被发现携带MFN 2基因编码的线粒体融合蛋白2的推定疾病突变。此外，MFN 2变异p.V705I在我们的患者中很常见，但我们提供的证据表明，这种先前描述的突变是一种常见的多态性，而不是致病性的。GDAP 1相关多发性神经病主要引起轻度和缓慢进展的表型。除小腿远端肌无力外，大多数患者表现为轻度的近端肌无力，常伴有不对称和高弓足。我们的研究结果拓宽了对CMT 2表型中GDAP 1突变的理解，并为在CMT基因诊断中使用全外显子组测序提供了支持。
We describe a founder mutation in the gene encoding ganglioside-induced differentiation associated-protein 1 (GDAP1), leading to amino acid change p.H123R, as a common cause of autosomal dominant axonal Charcot-Marie-Tooth (CMT2) neuropathy in Finland. The mutation explains up to 14 % of CMT2 in Finland, where most patients with axonal neuropathy have remained without molecular diagnosis. Only three families out of 28 were found to carry putative disease mutations in the MFN2 gene encoding mitofusin 2. In addition, the MFN2 variant p.V705I was commonly found in our patients, but we provide evidence that this previously described mutation is a common polymorphism and not pathogenic. GDAP1-associated polyneuropathy caused predominantly a mild and slowly progressive phenotype. Besides distal leg muscle weakness, most patients showed mild proximal weakness, often with asymmetry and pes cavus. Our findings broaden the understanding of GDAP1 mutations in CMT2 phenotypes and provide support for the use of whole-exome sequencing in CMT gene diagnostics.