Abstract：
Charcot-Marie-Tooth (CMT) disease is a neuromuscular disorder affecting the peripheral nervous system. The diagnostic yield in demyelinating CMT (CMT1) is typically ∼80-95%, of which at least 60% is due to the PMP22 gene duplication. The remainder of CMT1 is more genetically heterogeneous. We used whole exome and whole genome sequencing data included in the GENESIS database to investigate novel causal genes and mutations in a cohort of ∼2,670 individuals with CMT neuropathy. A recurrent heterozygous missense variant p.Thr1424Met in the recently described CMT gene ITPR3, encoding IP3R3 (inositol 1,4,5-trisphosphate receptor 3) was identified. This previously reported p.Thr1424Met change was present in 33 affected individuals from nine unrelated families from multiple populations, representing an unusual recurrence rate at a mutational hotspot, strengthening the gene-disease relationship (GnomADv4 allele frequency 1.76e-6). Sanger sequencing confirmed the co-segregation of the CMT phenotype with the presence of the mutation in autosomal dominant and de novo inheritance patterns, including a four-generation family with multiple affected second-degree cousins. Probands from all families presented with slow nerve conduction velocities, matching the diagnostic category of CMT1. Remarkably, we observed a uniquely variable clinical phenotype for age at onset and phenotype severity in p.Thr1424Met carrying patients, even within families. Finally, we present data supportive of a dominant-negative effect of the p.Thr1424Met mutation with associated changes in protein expression in patient-derived cells.
摘要：
Charcot-Marie-Tooth（CMT）疾病是一种影响周围神经系统的神经肌肉疾病。脱髓鞘CMT(CMT1)的诊断率通常为80-95%，其中至少60%是由于PMP22基因复制。CMT1的其余部分在遗传上更异质。我们使用GENESIS数据库中包含的全外显子组和全基因组测序数据，在约2,670名患有CMT神经病变的个体队列中调查新的致病基因和突变。在最近描述的CMT基因ITPR3中鉴定出一个重复的杂合错义变体p.Thr1424Met，编码IP3R3（肌醇1,4,5-三磷酸受体3）。先前报道的p.Thr1424Met变化存在于来自多个人群的9个无关家庭的33个受影响个体中，代表突变热点的异常复发率，加强基因-疾病关系(GnomADv4等位基因频率1.76e-6)。Sanger测序证实了CMT表型与常染色体显性遗传和从头遗传模式中存在突变的共分离。包括一个四代家庭，有多个受影响的二级表亲。来自所有家庭的前带神经传导速度慢，匹配CMT1的诊断类别。值得注意的是,我们在携带p.Thr1424Met的患者中观察到发病年龄和表型严重程度的唯一可变临床表型，甚至在家庭中。最后,我们提供的数据支持p.Thr1424Met突变的显性负效应以及患者来源细胞中蛋白质表达的相关变化.
