Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
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DOI：
10.1038/s41436-021-01194-x
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发表时间：
2021-06-17
影响因子：
8.8
通讯作者：
Wevers, Ron A.
中科院分区：
文献类型：
--
作者：
Wortmann, Saskia B.;Zietkiewicz, Szymon;Wevers, Ron A.
目的研究单等位基因CLPB变异体。许多基因中的致病性变异引起先天性中性粒细胞减少症。虽然大多数患者表现出孤立的血液学受累，但双等位基因CLPB变体是神经系统表型的基础，范围从非进行性智力残疾到产前脑病伴进行性脑萎缩、运动障碍、白内障、3-甲基戊烯二酸尿症和中性粒细胞减少症。CLPB最近被证明是一种线粒体再折叠酶;然而，确切的功能仍然难以捉摸。方法我们调查了来自三大洲四个国家的六名无关先证者，他们患有中性粒细胞减少症，并以癫痫、发育问题和3-甲基戊烯二酸尿症为主的表型，并进行了下一代测序。结果在每个个体中，我们鉴定出CLPB中四种不同的从头单等位基因错义变异之一。我们发现，这些变体干扰再折叠酶和在较小程度上ATP酶活性的CLPB在显性负性的方式。成纤维细胞中的复合体分析显示CLPB在非常高的分子量下与白藜芦醇苷共迁移。在对照成纤维细胞中，HAX 1主要作为单体迁移，而在患者样品中，在较高分子量处观察到多个HAX 1峰与CLPB共迁移，从而表明CLPB和HAX 1之间的相互作用持续时间更长。结论双等位基因和特异性单等位基因CLPB变体导致以神经发育延迟、癫痫发作和中性粒细胞减少为中心的表型谱，推测其通过HAX 1介导。
Purpose To investigate monoallelic CLPB variants. Pathogenic variants in many genes cause congenital neutropenia. While most patients exhibit isolated hematological involvement, biallelic CLPB variants underlie a neurological phenotype ranging from nonprogressive intellectual disability to prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, 3-methylglutaconic aciduria, and neutropenia. CLPB was recently shown to be a mitochondrial refoldase; however, the exact function remains elusive. Methods We investigated six unrelated probands from four countries in three continents, with neutropenia and a phenotype dominated by epilepsy, developmental issues, and 3-methylglutaconic aciduria with next-generation sequencing. Results In each individual, we identified one of four different de novo monoallelic missense variants in CLPB. We show that these variants disturb refoldase and to a lesser extent ATPase activity of CLPB in a dominant-negative manner. Complexome profiling in fibroblasts showed CLPB at very high molecular mass comigrating with the prohibitins. In control fibroblasts, HAX1 migrated predominantly as monomer while in patient samples multiple HAX1 peaks were observed at higher molecular masses comigrating with CLPB thus suggesting a longer-lasting interaction between CLPB and HAX1. Conclusion Both biallelic as well as specific monoallelic CLPB variants result in a phenotypic spectrum centered around neurodevelopmental delay, seizures, and neutropenia presumably mediated via HAX1.