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ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences

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ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences. / Sumathipala, Dulika; Strømme, Petter; Fattahi, Zohreh; Lüders, Torben; Sheng, Ying; Kahrizi, Kimia; Einarsen, Ingunn Holm; Sloan, Jennifer L; Najmabadi, Hossein; van den Heuvel, Lambert; Wevers, Ron A; Guerrero-Castillo, Sergio; Mørkrid, Lars; Valayannopoulos, Vassili; Backe, Paul Hoff; Venditti, Charles P; van Karnebeek, Clara D; Nilsen, Hilde; Frengen, Eirik; Misceo, Doriana.

in: BRAIN, Jahrgang 145, Nr. 7, 29.07.2022, S. 2602-2616.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Sumathipala, D, Strømme, P, Fattahi, Z, Lüders, T, Sheng, Y, Kahrizi, K, Einarsen, IH, Sloan, JL, Najmabadi, H, van den Heuvel, L, Wevers, RA, Guerrero-Castillo, S, Mørkrid, L, Valayannopoulos, V, Backe, PH, Venditti, CP, van Karnebeek, CD, Nilsen, H, Frengen, E & Misceo, D 2022, 'ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences', BRAIN, Jg. 145, Nr. 7, S. 2602-2616. https://doi.org/10.1093/brain/awac034

APA

Sumathipala, D., Strømme, P., Fattahi, Z., Lüders, T., Sheng, Y., Kahrizi, K., Einarsen, I. H., Sloan, J. L., Najmabadi, H., van den Heuvel, L., Wevers, R. A., Guerrero-Castillo, S., Mørkrid, L., Valayannopoulos, V., Backe, P. H., Venditti, C. P., van Karnebeek, C. D., Nilsen, H., Frengen, E., & Misceo, D. (2022). ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences. BRAIN, 145(7), 2602-2616. https://doi.org/10.1093/brain/awac034

Vancouver

Sumathipala D, Strømme P, Fattahi Z, Lüders T, Sheng Y, Kahrizi K et al. ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences. BRAIN. 2022 Jul 29;145(7):2602-2616. https://doi.org/10.1093/brain/awac034

Bibtex

@article{656a151309cc4d37829b71fa74eaa0ae,
title = "ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences",
abstract = "Bi-allelic pathogenic variants in ZBTB11 have been associated with intellectual developmental disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We have expanded the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions and described combined malonic and methylmalonic aciduria as a biochemical manifestation. As ZBTB11 encodes for a transcriptional regulator, we performeded chromatin immunoprecipitation-sequencing targeting ZBTB11 in fibroblasts from patients and controls. Chromatin immunoprecipitation-sequencing revealed binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 showed reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. Most of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts revealed dysregulation of mitochondrial functions. In addition, we uncovered that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining combined malonic and methylmalonic aciduria. Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.",
keywords = "Amino Acid Metabolism, Inborn Errors/genetics, Brain, Humans, Metabolism, Inborn Errors/genetics, Nervous System Malformations",
author = "Dulika Sumathipala and Petter Str{\o}mme and Zohreh Fattahi and Torben L{\"u}ders and Ying Sheng and Kimia Kahrizi and Einarsen, {Ingunn Holm} and Sloan, {Jennifer L} and Hossein Najmabadi and {van den Heuvel}, Lambert and Wevers, {Ron A} and Sergio Guerrero-Castillo and Lars M{\o}rkrid and Vassili Valayannopoulos and Backe, {Paul Hoff} and Venditti, {Charles P} and {van Karnebeek}, {Clara D} and Hilde Nilsen and Eirik Frengen and Doriana Misceo",
note = "{\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.",
year = "2022",
month = jul,
day = "29",
doi = "10.1093/brain/awac034",
language = "English",
volume = "145",
pages = "2602--2616",
journal = "BRAIN",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "7",

}

RIS

TY - JOUR

T1 - ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences

AU - Sumathipala, Dulika

AU - Strømme, Petter

AU - Fattahi, Zohreh

AU - Lüders, Torben

AU - Sheng, Ying

AU - Kahrizi, Kimia

AU - Einarsen, Ingunn Holm

AU - Sloan, Jennifer L

AU - Najmabadi, Hossein

AU - van den Heuvel, Lambert

AU - Wevers, Ron A

AU - Guerrero-Castillo, Sergio

AU - Mørkrid, Lars

AU - Valayannopoulos, Vassili

AU - Backe, Paul Hoff

AU - Venditti, Charles P

AU - van Karnebeek, Clara D

AU - Nilsen, Hilde

AU - Frengen, Eirik

AU - Misceo, Doriana

N1 - © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2022/7/29

Y1 - 2022/7/29

N2 - Bi-allelic pathogenic variants in ZBTB11 have been associated with intellectual developmental disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We have expanded the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions and described combined malonic and methylmalonic aciduria as a biochemical manifestation. As ZBTB11 encodes for a transcriptional regulator, we performeded chromatin immunoprecipitation-sequencing targeting ZBTB11 in fibroblasts from patients and controls. Chromatin immunoprecipitation-sequencing revealed binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 showed reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. Most of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts revealed dysregulation of mitochondrial functions. In addition, we uncovered that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining combined malonic and methylmalonic aciduria. Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.

AB - Bi-allelic pathogenic variants in ZBTB11 have been associated with intellectual developmental disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We have expanded the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions and described combined malonic and methylmalonic aciduria as a biochemical manifestation. As ZBTB11 encodes for a transcriptional regulator, we performeded chromatin immunoprecipitation-sequencing targeting ZBTB11 in fibroblasts from patients and controls. Chromatin immunoprecipitation-sequencing revealed binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 showed reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. Most of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts revealed dysregulation of mitochondrial functions. In addition, we uncovered that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining combined malonic and methylmalonic aciduria. Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.

KW - Amino Acid Metabolism, Inborn Errors/genetics

KW - Brain

KW - Humans

KW - Metabolism, Inborn Errors/genetics

KW - Nervous System Malformations

U2 - 10.1093/brain/awac034

DO - 10.1093/brain/awac034

M3 - SCORING: Journal article

C2 - 35104841

VL - 145

SP - 2602

EP - 2616

JO - BRAIN

JF - BRAIN

SN - 0006-8950

IS - 7

ER -