Motley William W, Züchner Stephan, Scherer Steven S
Department of Neurology (W.W.M., S.S.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Human Genetics (S.Z.), Hussman Institute for Human Genomics, University of Miami, FL.
Neurol Genet. 2020 Jul 31;6(5):e496. doi: 10.1212/NXG.0000000000000496. eCollection 2020 Oct.
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 (), 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 mutations, and provide further evidence that BPAG1 plays an essential role in axonal health.
在一个有两名患病同胞的小家庭中确定轴索性夏科-马里-图思病的遗传病因，其中一名同胞在检查时有小脑特征。
对基因组DNA进行全外显子组测序，并分析隐性遗传突变；对转录本进行基于聚合酶链反应的信使核糖核酸/互补脱氧核糖核酸分析，以表征外显子组测序鉴定出的变异的影响。
我们在张力蛋白（）中鉴定出复合杂合突变，该蛋白经可变剪接产生许多斑块蛋白家族连接蛋白（命名为大疱性类天疱疮抗原1 [BPAG1]蛋白），其功能是连接细胞骨架丝网络。一个突变（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2型异构体；另一个突变（c.8283+1G>A）使共有剪接供体位点发生突变，导致所有BPAG1a和BPAG1b异构体的血影蛋白重复结构域出现22个氨基酸的框内缺失。
这些发现引入了一种新的人类表型，即隐性突变导致的轴索性夏科-马里-图思病，并提供了进一步证据表明BPAG1在轴突健康中起重要作用。
