Results

RDF/XMLNTriplesTurtleShow queryShare ▶
SubjectPredicateObject
http://purl.uniprot.org/citations/34140661http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/34140661http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/34140661http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.org/dc/terms/identifier"doi:10.1038/s41436-021-01194-x"xsd:string
http://purl.uniprot.org/citations/34140661http://purl.org/dc/terms/identifier"doi:10.1038/s41436-021-01194-x"xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Wagner M."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Wagner M."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Venselaar H."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Venselaar H."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Christodoulou J."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Christodoulou J."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Wevers R.A."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Wevers R.A."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Mayr J.A."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Mayr J.A."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Prada C.E."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Prada C.E."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Feichtinger R.G."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Feichtinger R.G."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Wolf N.I."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Wolf N.I."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Russell J."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Russell J."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Cabrera-Orefice A."xsd:string
http://purl.uniprot.org/citations/34140661http://purl.uniprot.org/core/author"Cabrera-Orefice A."xsd:string
▶