A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy
A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy
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DOI：
10.1093/hmg/ddr471
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发表时间：
2012-01-15
影响因子：
3.5
通讯作者：
Baas, Frank
中科院分区：
文献类型：
--
作者：
Weterman, Marian A. J.;Sorrentino, Vincenzo;Baas, Frank
尽管在遗传性多发性神经病/腓骨肌萎缩症（CMT）中鉴定出大量基因，但许多家族中的遗传缺陷仍然未知。在这里，我们报告了一个新的常染色体显性轴突神经病基因的鉴定在一个大的三代家庭。连锁分析鉴定了9 q33 -34上的5 Mb区域，LOD评分为5.12。对目标区域的序列捕获和下一代测序鉴定了5个先前未报告的非同义杂合单核苷酸变化或插入缺失，其中4个通过桑格测序证实。两个序列变异与疾病共分离，一个是LRSAM 1最后一个外显子中的2 bp插入，在676个种族匹配的对照染色体中也不存在。该移码突变（p.Leu708Argfx28）位于编码蛋白的C-末端RING指基序中。在具有携带患者突变的构建体的转染细胞中，泛素连接酶活性受到影响，如通过更高水平的TSG 101丰度所测量的，TSG 101是唯一报道的LRSAM 1靶标。注射的吗啉代寡核苷酸在斑马鱼胚胎中直接对ATG或最后剪接位点的斑马鱼Lrsam 1扰乱神经发育，表现出较低的组织神经结构，此外，影响尾巴的形成和运动。LRSAM 1在成人脊髓运动神经元以及胎儿脊髓和肌肉组织中高度表达。最近，LRSAM 1的纯合突变被认为是一个隐性轴突性多发性神经病家族中该疾病的有力候选者。我们的数据强烈支持LRSAM 1突变可以导致显性和隐性形式的CMT的假设。
Despite the high number of genes identified in hereditary polyneuropathies/Charcot-Marie-Tooth (CMT) disease, the genetic defect in many families is still unknown. Here we report the identification of a new gene for autosomal dominant axonal neuropathy in a large three-generation family. Linkage analysis identified a 5 Mb region on 9q33-34 with a LOD score of 5.12. Sequence capture and next-generation sequencing of the region of interest identified five previously unreported non-synonymous heterozygous single nucleotide changes or indels, four of which were confirmed by Sanger sequencing. Two sequence variants co-segregated with the disease, and one, a 2 bp insertion in the last exon of LRSAM1, was also absent in 676 ethnicity-matched control chromosomes. This frameshift mutation (p.Leu708Argfx28) is located in the C-terminal RING finger motif of the encoded protein. Ubiquitin ligase activity in transfected cells with constructs carrying the patient mutation was affected as measured by a higher level of abundance of TSG101, the only reported target of LRSAM1. Injections of morpholino oligonucleotides in zebrafish embryos directed against the ATG or last splice site of zebrafish Lrsam1 disturbed neurodevelopment, showing a less organized neural structure and, in addition, affected tail formation and movement. LRSAM1 is highly expressed in adult spinal cord motoneurons as well as in fetal spinal cord and muscle tissue. Recently, a homozygous mutation in LRSAM1 was proposed as a strong candidate for the disease in a family with recessive axonal polyneuropathy. Our data strongly support the hypothesis that LRSAM1 mutations can cause both dominant and recessive forms of CMT.