Mutations in PNKP Cause Recessive Ataxia with Oculomotor Apraxia Type 4
Mutations in PNKP Cause Recessive Ataxia with Oculomotor Apraxia Type 4
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DOI：
10.1016/j.ajhg.2015.01.005
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发表时间：
2015-03-05
影响因子：
9.8
通讯作者：
Guerreiro, Rita
中科院分区：
文献类型：
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作者：
Bras, Jose;Alonso, Isabel;Guerreiro, Rita
遗传性常染色体隐性小脑共济失调是一组遗传和临床异质性疾病。我们使用纯合性作图和外显子组测序研究了一个队列的9个葡萄牙家庭谁被确定在全国范围内，人口为基础的，系统的调查，表现出一致的隐性共济失调与眼神经失用症（AOA）的表型。整合这些分析的数据，在三个研究的家族中鉴定出相同的纯合PNKP（多核苷酸激酶30-磷酸酶）突变，c.1123G>T（p.Gly375Trp）。当分析来自剩余队列的外显子组测序数据中的这个特定基因时，我们在其他五个家庭中鉴定了纯合或复合杂合突变。PNKP是一种双功能酶，在DNA损伤修复的不同途径中发挥关键作用。该基因的突变以前与常染色体隐性综合征有关，其特征为小头畸形;早发性难治性癫痫发作;和发育迟缓（MCSZ）。与隐性AOA相关的PNKP突变的发现扩展了与该基因相关的表型，并确定了导致AOA的第四个位点。这些数据证实MCSZ和某些形式的共济失调具有共同的病因学特征，很可能反映了PNKP在DNA修复机制中的作用。
Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 30-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms.