Postnatal Microcephaly and Pain Insensitivity Due to a De Novo Heterozygous DNM1L Mutation Causing Impaired Mitochondrial Fission and Function
Postnatal Microcephaly and Pain Insensitivity Due to a De Novo Heterozygous DNM1L Mutation Causing Impaired Mitochondrial Fission and Function
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DOI：
10.1002/ajmg.a.37624
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发表时间：
2016-06-01
影响因子：
2
通讯作者：
Saada, Ann
中科院分区：
文献类型：
--
作者：
Sheffer, Ruth;Douiev, Liza;Saada, Ann
一类新兴的线粒体疾病是由影响线粒体动力学和功能的核基因突变引起的。其中之一是编码动力蛋白相关蛋白1 （DRP1）的DNM1L基因，它在线粒体裂变过程中起着关键作用。在这里，我们描述了一个病人与一个新的显性阴性，从头DNM1L突变，扩大了临床谱。本例患者表现为慢性神经系统疾病，以出生后小头畸形、发育迟缓和疼痛不敏感为特征。肌肉活检显示呼吸链复合体IV活性降低。外显子组测序显示一个从头杂合c.1084G> a （p.G362S）突变。随后对患者皮肤成纤维细胞的研究显示，线粒体分裂和部分呼吸链缺陷明显受损，而过氧化物酶体形态保持完整。过表达突变基因DNM1L的人包皮成纤维细胞表现出异常的线粒体形态。(C) 2016 Wiley期刊公司
An emerging class of mitochondrial disorders is caused by mutations in nuclear genes affecting mitochondrial dynamics and function. One of these is the DNM1L gene encoding the dynamin-related protein 1 (DRP1), which is pivotal in the mitochondrial fission process. Here, we describe a patient with a novel dominant-negative, de novo DNM1L mutation, which expands the clinical spectrum. The patient reported here exhibits a chronic neurological disorder, characterized by postnatal microcephaly, developmental delay, and pain insensitivity. Muscle biopsy disclosed decreased respiratory chain complex IV activity. Exome sequencing showed a de novo heterozygous c.1084G>A (p.G362S) mutation. Subsequent studies of patient skin fibroblasts showed markedly impaired mitochondrial fission and a partial respiratory chain defect while peroxisomal morphology remained intact. Human foreskin fibroblasts over-expressing the mutant DNM1L gene displayed aberrant mitochondrial morphology. (C) 2016 Wiley Periodicals, Inc.