Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy
Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy
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DOI：
10.1093/hmg/ddp014
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Hannibal, Mark C.
中科院分区：
文献类型：
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作者：
Landsverk, Megan L.;Ruzzo, Elizabeth K.;Hannibal, Mark C.
遗传性神经痛性肌萎缩症（HNA）是一种常染色体显性遗传病，与主要影响臂丛的局灶性神经病变反复发作相关。在一些家系中，SEPT9基因的点突变已被确定为海航的分子基础。然而，在许多家庭中，包括那些来自北美的家庭，显示出基因创始单倍型，没有检测到序列突变。我们报告了在12个具有共同创始人单倍型的北美家庭中与海航相关的基因内38 Kb SEPT9重复。断点分析表明，该重复在所有家系中都是相同的，分子分析显示，该重复包括先前发现HNA突变的645 bp外显子。跨越该重复的SEPT9转录物变体包含该外显子的两个帧内重复，免疫印迹显示更大分子量的SEPT9蛋白亚型。该外显子还编码大部分SEPT9 n端脯氨酸丰富区域，表明该区域在海航的发病机制中起作用。
Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with recurrent episodes of focal neuropathy primarily affecting the brachial plexus. Point mutations in the SEPT9 gene have been previously identified as the molecular basis of HNA in some pedigrees. However in many families, including those from North America demonstrating a genetic founder haplotype, no sequence mutations have been detected. We report an intragenic 38 Kb SEPT9 duplication that is linked to HNA in 12 North American families that share the common founder haplotype. Analysis of the breakpoints showed that the duplication is identical in all pedigrees, and molecular analysis revealed that the duplication includes the 645 bp exon in which previous HNA mutations were found. The SEPT9 transcript variants that span this duplication contain two in-frame repeats of this exon, and immunoblotting demonstrates larger molecular weight SEPT9 protein isoforms. This exon also encodes for a majority of the SEPT9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA.