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.

中文翻译：

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中性粒细胞减少症和智力障碍是双等位基因和从头 CLPB 缺乏症的标志

目的

研究单等位基因CLPB变体。许多基因的致病变异导致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变异是神经学表型的基础，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重折叠酶。然而，确切的功能仍然难以捉摸。

方法

我们通过下一代测序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和以癫痫、发育问题和 3-甲基戊二酸尿症为主的表型。

结果

在每个个体中，我们在CLPB中鉴定了四种不同的从头单等位基因错义变体之一。我们表明这些变体以显性负向方式干扰重折叠酶和较小程度的 CLPB 的 ATP 酶活性。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抑制素一起迁移。在对照成纤维细胞中，HAX1 主要作为单体迁移，而在患者样本中，在与 CLPB 迁移的较高分子量处观察到多个 HAX1 峰，因此表明 CLPB 和 HAX1 之间存在更持久的相互作用。

结论

双等位基因和特定的单等位基因CLPB变体均导致表型谱以神经发育迟缓、癫痫发作和中性粒细胞减少为中心，可能通过 HAX1 介导。