Novel biallelic mutations in the PNPT1 gene encoding a mitochondrial-RNA-import protein PNPase cause delayed myelination
Novel biallelic mutations in the PNPT1 gene encoding a mitochondrial-RNA-import protein PNPase cause delayed myelination
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DOI：
10.1111/cge.13068
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发表时间：
2018-02-01
影响因子：
3.5
通讯作者：
Kure, S.
中科院分区：
文献类型：
--
作者：
Sato, R.;Arai-Ichinoi, N.;Kure, S.
最近的研究表明，小RNA的转录或线粒体翻译受损可导致异常的髓鞘形成。PNPT1编码的一种多核苷酸磷酸化酶(PNPase)促进小RNA进入线粒体。已有报道在伴有线粒体功能障碍的神经发育疾病患者中发现PNPT1突变。我们在这里报告两个PNPT1突变的兄弟姐妹，他们表现出髓鞘形成延迟和线粒体功能障碍。我们通过四元组全外显子测序鉴定了PNPT1的复合杂合突变(c.227G>；A；p.Gly76Asp和c.574C>；T；p.Arg192*)。对患者皮肤成纤维细胞的分析表明，PNPase的表达明显减少，小RNARNaseP进入线粒体的能力受到损害。野生型PNPT1的外源表达，而不是突变体，挽救了患者皮肤成纤维细胞中ATP的产生，表明已识别的突变具有致病性。我们的病例扩大了PNPT1突变的表型谱，这可能导致髓鞘形成延迟。
Recent studies suggest that impaired transcription or mitochondrial translation of small RNAs can cause abnormal myelination. A polynucleotide phosphorylase (PNPase) encoded by PNPT1 facilitates the import of small RNAs into mitochondria. PNPT1 mutations have been reported in patients with neurodevelopmental diseases with mitochondrial dysfunction. We report here 2 siblings with PNPT1 mutations who presented delayed myelination as well as mitochondrial dysfunction. We identified compound heterozygous mutations (c.227G>A; p.Gly76Asp and c.574C>T; p.Arg192*) in PNPT1 by quartet whole-exome sequencing. Analyses of skin fibroblasts from the patient showed that PNPase expression was markedly decreased and that import of the small RNARNaseP into mitochondria was impaired. Exogenous expression of wild-type PNPT1, but not mutants, rescued ATP production in patient skin fibroblasts, suggesting the pathogenicity of the identified mutations. Our cases expand the phenotypic spectrum of PNPT1 mutations that can cause delayed myelination.