To determine the genetic cause of axonal Charcot-Marie-Tooth disease in a small family with 2 affected siblings, one of whom had cerebellar features on examination.

Whole-exome sequencing of genomic DNA and analysis for recessively inherited mutations; PCR-based messenger RNA/complementary DNA analysis of transcripts to characterize the effects of variants identified by exome sequencing.

We identified compound heterozygous mutations in dystonin (DST), which is alternatively spliced to create many plakin family linker proteins (named the bullous pemphigoid antigen 1 [BPAG1] proteins) that function to bridge cytoskeletal filament networks. One mutation (c.250C>T) is predicted to cause a nonsense mutation (p.R84X) that only affects isoform 2 variants, which have an N-terminal transmembrane domain; the other (c.8283+1G>A) mutates a consensus splice donor site and results in a 22 amino acid in-frame deletion in the spectrin repeat domain of all BPAG1a and BPAG1b isoforms.

These findings introduce a novel human phenotype, axonal Charcot-Marie-Tooth, of recessive DST mutations, and provide further evidence that BPAG1 plays an essential role in axonal health.

在一个有 2 个受影响的兄弟姐妹的小家庭中确定轴突 Charcot-Marie-Tooth 病的遗传原因，其中一个在检查时具有小脑特征。

基因组 DNA 的全外显子组测序和隐性遗传突变分析；基于 PCR 的信使 RNA/转录本互补 DNA 分析，以表征通过外显子组测序鉴定的变体的影响。

我们鉴定了肌张力障碍 ( DST ) 中的复合杂合突变，该突变被交替剪接以产生许多 plakin 家族接头蛋白（称为大疱性类天疱疮抗原 1 [BPAG1] 蛋白），这些蛋白可起到桥接细胞骨架丝网络的作用。一种突变 (c.250C>T) 预计会导致无义突变 (p.R84X)，该突变仅影响具有 N 端跨膜结构域的同工型 2 变体；另一个 (c.8283+1G>A) 突变了一个共有剪接供体位点，并导致所有 BPAG1a 和 BPAG1b 同种型的血影蛋白重复结构域中的 22 个氨基酸框内缺失。

这些发现引入了一种新的人类表型，即隐性DST突变的轴突 Charcot-Marie-Tooth，并进一步证明 BPAG1 在轴突健康中起重要作用。