Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family. Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3′-phosphatase (PNKP) gene. It encodes a DNA repair protein recently associated with recessive ataxia with oculomotor apraxia type 4 (AOA4) and microcephaly, seizures, and developmental delay (MCSZ). Subsequently, five unrelated Costa Rican CMT2 subjects initially identified as being heterozygous for the same MED25 variant were found to be also compound heterozygote for PNKP. All were heterozygous for the same variant found homozygous in the large family and a second one previously associated with ataxia (p.Thr408del). Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay. We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect.

中文翻译：

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多核苷酸激酶3'-磷酸酶基因（PNKP）与先前与MED25有关的Charcot-Marie-Tooth病（CMT2B2）有关。

Charcot-Marie-Tooth病（CMT）代表遗传性周围神经病的异质性组。我们先前曾报道在一个大型哥斯达黎加家庭中，该疾病与染色体19q13.3上的CMT基因座分离，并带有轴突神经病和遗传的常染色体隐性遗传（CMT2B2）。我们提出了介导复合体25（MED25）基因中的纯合性错义变异作为该病的病因。然而，事实上没有其他CMT患者患有MED25迄今为止，已经报道了多种变体，这使我们重新评估了原始家族。使用外显子组测序，我们现在在相邻基因的最后一个外显子，即多核苷酸激酶3'-磷酸酶（PNKP）基因中鉴定了纯合性无义变体（p.Gln517ter）。它编码一种最近与隐性共济失调相关的DNA修复蛋白，后者伴有动眼性失用症4型（AOA4）和小头畸形，癫痫发作和发育迟缓（MCSZ）。随后，发现最初被鉴定为同一MED25变体杂合的五名无关的哥斯达黎加CMT2受试者也是PNKP的复合杂合子。对于在大家族中发现的纯合子和先前与共济失调有关的第二个变种（p.Thr408del），所有这些都是杂合的。最初的家庭和新个体的详细临床重新评估显示，所有成年发作的缓慢进行性CMT2均伴有小脑功能障碍的迹象，例如口齿不清和动眼神经受累，但无小头畸形，癫痫发作或发育迟缓。我们提出，PKNP变异体是这些个体中CMT2表型的主要致病变异体，且较温和的临床表现是由于等位基因作用所致。