Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency
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Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency. / Wortmann, Saskia B; Ziętkiewicz, Szymon; Guerrero-Castillo, Sergio; Feichtinger, René G; Wagner, Matias; Russell, Jacqui; Ellaway, Carolyn; Mróz, Dagmara; Wyszkowski, Hubert; Weis, Denisa; Hannibal, Iris; von Stülpnagel, Celina; Cabrera-Orefice, Alfredo; Lichter-Konecki, Uta; Gaesser, Jenna; Windreich, Randy; Myers, Kasiani C; Lorsbach, Robert; Dale, Russell C; Gersting, Søren; Prada, Carlos E; Christodoulou, John; Wolf, Nicole I; Venselaar, Hanka; Mayr, Johannes A; Wevers, Ron A.
in: GENET MED, Jahrgang 23, Nr. 9, 09.2021, S. 1705-1714.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 - © 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
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.
KW - Adaptor Proteins, Signal Transducing
KW - Brain Diseases
KW - Epilepsy
KW - Humans
KW - Intellectual Disability/genetics
KW - Metabolism, Inborn Errors
KW - Neutropenia/genetics
U2 - 10.1038/s41436-021-01194-x
DO - 10.1038/s41436-021-01194-x
M3 - SCORING: Journal article
C2 - 34140661
VL - 23
SP - 1705
EP - 1714
JO - GENET MED
JF - GENET MED
SN - 1098-3600
IS - 9
ER -