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Wortmann, S.B.* ; Zietkiewicz, S.* ; Guerrero-Castillo, S.* ; Feichtinger, R.G.* ; Wagner, M. ; Russell, J.* ; Ellaway, C.* ; Mróz, D.* ; Wyszkowski, H.* ; Weis, D.* ; Hannibal, I.* ; von Stülpnagel, C.* ; Cabrera-Orefice, A.* ; Lichter-Konecki, U.* ; Gaesser, J.* ; Windreich, R.* ; Myers, K.C.* ; Lorsbach, R.* ; Dale, R.C.* ; Gersting, S.* ; Prada, C.E.* ; Christodoulou, J.* ; Wolf, N.I.* ; Venselaar, H.* ; Mayr, J.A.* ; Wevers, R.A.*

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

Genet. Med. 23, 1705-1714 (2021)
Publ. Version/Full Text Postprint DOI PMC
Open Access Green
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Protein; Mutations; Substrate; Domain; Hsp104
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Journal Genetics in Medicine
Quellenangaben Volume: 23, Issue: 9, Pages: 1705-1714 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Baltimore, Md.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants New South Wales Office of Health and Medical Research Sydney Genomics Collaborative grant
Victorian Government's Operational Infrastructure Support Program
Royal Children's Hospital Foundation