Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
21
09
2020
accepted:
15
04
2021
revised:
15
04
2021
pubmed:
19
6
2021
medline:
21
10
2021
entrez:
18
6
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 34140661
doi: 10.1038/s41436-021-01194-x
pii: S1098-3600(21)05097-8
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
HAX1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1705-1714Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
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