TY - JOUR
T1 - Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
AU - Wortmann, Saskia B.
AU - Ziętkiewicz, Szymon
AU - Guerrero-Castillo, Sergio
AU - Feichtinger, René G.
AU - Wagner, Matias
AU - Russell, Jacqui
AU - Ellaway, Carolyn
AU - Mróz, Dagmara
AU - Wyszkowski, Hubert
AU - Weis, Denisa
AU - Hannibal, Iris
AU - von Stülpnagel, Celina
AU - Cabrera-Orefice, Alfredo
AU - Lichter-Konecki, Uta
AU - Gaesser, Jenna
AU - Windreich, Randy
AU - Myers, Kasiani C.
AU - Lorsbach, Robert
AU - Dale, Russell C.
AU - Gersting, Søren
AU - Prada, Carlos E.
AU - Christodoulou, John
AU - Wolf, Nicole I.
AU - Venselaar, Hanka
AU - Mayr, Johannes A.
AU - Wevers, Ron A.
N1 - Funding Information: Research relating to P5 was supported by a New South Wales Office of Health and Medical Research Sydney Genomics Collaborative grant and the Victorian Government’s Operational Infrastructure Support Program. We thank the Kinghorn Centre for Clinical Genomics and Lisa Riley (Children’s Hospital at Westmead, Australia) for assistance with genome sequencing and Helen Cashman (South Eastern Sydney Local Health District, Sydney, Australia) for providing the blood film images for P5. The Chair in Genomic Medicine awarded to John Christodoulou is generously supported by The Royal Children’s Hospital Foundation Publisher Copyright: © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108056903&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41436-021-01194-x
DO - https://doi.org/10.1038/s41436-021-01194-x
M3 - Article
C2 - 34140661
SN - 1098-3600
VL - 23
SP - 1705
EP - 1714
JO - Genetics in medicine
JF - Genetics in medicine
IS - 9
ER -