ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 38 citations in OpenAlex.
- CLPB deficiency-associated congenital neutropenia: A rare case report and literature review.Medicine · 2026Review
- Neuronal mitochondrial disaggregase CLPB ameliorates Huntington's disease pathology in mice.Theranostics · 2026Article
- High-resolution native electrophoresis in-gel activity assay reveals biological insights of medium-chain fatty acyl-CoA dehydrogenase deficiency.Scientific reports · 2025Article
- Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.Biochemical Society transactions · 2025Article
- CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.Journal of inherited metabolic disease · 2025Review
- Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.Nature communications · 2025Article
- Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.Apoptosis : an international journal on programmed cell death · 2025Article
- CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.The Journal of cell biology · 2024Article
- The metabolic basis of inherited neutropenias.British journal of haematology · 2024Review
- Let's make it clear: systematic exploration of mitochondrial DNA- and RNA-protein complexes by complexome profiling.Nucleic acids research · 2023Article
- Dodecamer assembly of a metazoan AAAScience advances · 2023Article
- Article
- Mitochondrial biology and dysfunction in secondary mitochondrial disease.Open biology · 2022Review
- Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights.The Journal of clinical endocrinology and metabolism · 2022Article
- Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3.Cell reports · 2022Article
- Review
- How to proceed after "negative" exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques.Journal of inherited metabolic disease · 2022Review
- HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.The Journal of clinical investigation · 2022Article
- Biallelic CLPB mutation associated with isolated neutropenia and 3-MGA-uria.Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology · 2022Article
- Human mitochondrial AAA+ ATPase SKD3/CLPB assembles into nucleotide-stabilized dodecamers.Biochemical and biophysical research communications · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
26 authors at 13 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeTo 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.
methodsWe 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.
resultsIn 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.
conclusionBoth 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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