Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency

SB Wortmann, S Ziętkiewicz, S Guerrero-Castillo… - Genetics in …, 2021 - nature.com
SB Wortmann, S Ziętkiewicz, S Guerrero-Castillo, RG Feichtinger, M Wagner, J Russell…
Genetics in Medicine, 2021nature.com
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 …
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.
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