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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, Vol. 23, No. 9, 09.2021, p. 1705-1714.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Wortmann, SB, Ziętkiewicz, S, Guerrero-Castillo, S, Feichtinger, RG, 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, KC, Lorsbach, R, Dale, RC, Gersting, S, Prada, CE, Christodoulou, J, Wolf, NI, Venselaar, H, Mayr, JA & Wevers, RA 2021, 'Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency', GENET MED, vol. 23, no. 9, pp. 1705-1714. https://doi.org/10.1038/s41436-021-01194-x

APA

Wortmann, S. B., Ziętkiewicz, 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., ... Wevers, R. A. (2021). Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency. GENET MED, 23(9), 1705-1714. https://doi.org/10.1038/s41436-021-01194-x

Vancouver

Wortmann SB, Ziętkiewicz S, Guerrero-Castillo S, Feichtinger RG, Wagner M, Russell J et al. Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency. GENET MED. 2021 Sep;23(9):1705-1714. https://doi.org/10.1038/s41436-021-01194-x

Bibtex

@article{d8735544ce644c729da598a598ede2cf,
title = "Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency",
abstract = "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.",
keywords = "Adaptor Proteins, Signal Transducing, Brain Diseases, Epilepsy, Humans, Intellectual Disability/genetics, Metabolism, Inborn Errors, Neutropenia/genetics",
author = "Wortmann, {Saskia B} and Szymon Zi{\c e}tkiewicz and Sergio Guerrero-Castillo and Feichtinger, {Ren{\'e} G} and Matias Wagner and Jacqui Russell and Carolyn Ellaway and Dagmara Mr{\'o}z and Hubert Wyszkowski and Denisa Weis and Iris Hannibal and {von St{\"u}lpnagel}, Celina and Alfredo Cabrera-Orefice and Uta Lichter-Konecki and Jenna Gaesser and Randy Windreich and Myers, {Kasiani C} and Robert Lorsbach and Dale, {Russell C} and S{\o}ren Gersting and Prada, {Carlos E} and John Christodoulou and Wolf, {Nicole I} and Hanka Venselaar and Mayr, {Johannes A} and Wevers, {Ron A}",
note = "{\textcopyright} 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.",
year = "2021",
month = sep,
doi = "10.1038/s41436-021-01194-x",
language = "English",
volume = "23",
pages = "1705--1714",
journal = "GENET MED",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

RIS

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 -