Mutations in FBXL4, Encoding a Mitochondrial Protein, Cause Early-Onset Mitochondrial Encephalomyopathy
Mutations in FBXL4, Encoding a Mitochondrial Protein, Cause Early-Onset Mitochondrial Encephalomyopathy
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DOI：
10.1016/j.ajhg.2013.07.016
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发表时间：
2013-09-05
影响因子：
9.8
通讯作者：
Zeviani, Massimo
中科院分区：
文献类型：
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作者：
Gai, Xiaowu;Ghezzi, Daniele;Zeviani, Massimo
全外显子组测序和同源性作图研究，在有缺陷的组合线粒体OXPHOS酶缺乏症的受试者中独立进行，在7个不相关的线粒体疾病家族中确定了总共9个疾病隔离FBXL4突变，由6个单例和3个兄弟姐妹组成。所有受试者均表现出早发性乳酸血症、肌张力减退和严重脑肌病引起的发育迟缓，这些症状与进行性脑萎缩和白色物质、深灰色核和脑干结构的不同累及一致。广泛的其他多系统特征，包括畸形，骨骼异常，生长不良，胃肠道动力障碍，肾小管酸中毒，癫痫发作和间歇性代谢衰竭。线粒体呼吸链缺陷存在于所有测试个体的肌肉或成纤维细胞中，同时显著降低的耗氧率和培养细胞中线粒体网络的过度碎片化。在几个受试者的肌肉和成纤维细胞中，观察到mtDNA含量大幅下降。FBXL4是F-box蛋白家族的成员，其中一些参与磷酸化依赖性泛素化和/或G蛋白受体偶联。我们还证明，FBXL4是针对线粒体和定位在膜间隙，在那里它参与了一个约400 kDa的蛋白质复合物。这些数据强烈支持FBXL4在控制生物能量稳态和mtDNA维持中的作用。FBXL4突变是婴儿早期线粒体脑肌病发作的复发原因。
Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400 kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy.