Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation
Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation
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DOI：
10.1007/s10545-015-9813-0
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发表时间：
2015-03-01
影响因子：
4.2
通讯作者：
Rahman, Shamima
中科院分区：
文献类型：
--
作者：
Kanabus, Marta;Shahni, Rojeen;Rahman, Shamima
全外显子组测序被用来调查线粒体疾病的遗传原因，在两个兄弟姐妹与先天性板层白内障综合征相关的肾钙质沉着症，髓质囊肿和3-甲基戊烯二酸尿症。假设编码一种靶向蛋白的基因为常染色体隐性遗传;符合这些标准的唯一变体是CLPB基因中的c.1882C > T（p.Arg628Cys）和c.1915G > A（p.Glu639Lys），编码一种负责解聚线粒体和胞质蛋白的热休克蛋白/伴侣蛋白。功能研究，包括定量PCR（qPCR）和蛋白质印迹，支持这些突变的致病性。此外，分子模型表明，突变破坏亚基之间的相互作用，使CLPB六聚体不能形成或不稳定，从而削弱其作为蛋白质解聚酶的作用。我们的结论是蛋白质聚集体的积累是CLPB缺乏症的白内障和肾钙质沉着症的基础，CLPB缺乏症是3-甲基戊烯二酸尿症的一种新的遗传原因。3-甲基戊烯二酸尿症的常见线粒体原因似乎是线粒体膜结构的破坏，如Barth综合征（tafazzin缺乏症）、Syndrome综合征（酰基甘油激酶缺乏症）和MEGDEL综合征（由于SERAC 1突变导致线粒体膜脂质重塑受损）。我们现在提出，异常蛋白质聚集体对线粒体膜的扰动导致CLPB缺乏症的3-甲基戊烯二酸尿症。
Whole exome sequencing was used to investigate the genetic cause of mitochondrial disease in two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria. Autosomal recessive inheritance in a gene encoding a mitochondrially targeted protein was assumed; the only variants which satisfied these criteria were c.1882C > T (p.Arg628Cys) and c.1915G > A (p.Glu639Lys) in the CLPB gene, encoding a heat shock protein/chaperonin responsible for disaggregating mitochondrial and cytosolic proteins. Functional studies, including quantitative PCR (qPCR) and Western blot, support pathogenicity of these mutations. Furthermore, molecular modelling suggests that the mutations disrupt interactions between subunits so that the CLPB hexamer cannot form or is unstable, thus impairing its role as a protein disaggregase. We conclude that accumulation of protein aggregates underlies the development of cataracts and nephrocalcinosis in CLPB deficiency, which is a novel genetic cause of 3-methylglutaconic aciduria. A common mitochondrial cause for 3-methylglutaconic aciduria appears to be disruption of the architecture of the mitochondrial membranes, as in Barth syndrome (tafazzin deficiency), Sengers syndrome (acylglycerol kinase deficiency) and MEGDEL syndrome (impaired remodelling of the mitochondrial membrane lipids because of SERAC1 mutations). We now propose that perturbation of the mitochondrial membranes by abnormal protein aggregates leads to 3-methylglutaconic aciduria in CLPB deficiency.