TY - JOUR
T1 - ZBTB11 dysfunction
T2 - 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 - Publisher Copyright: © 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2022/7/1
Y1 - 2022/7/1
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 - RNA-sequencing
KW - ZBTB11
KW - chromatin immunoprecipitation (ChIP)-sequencing
KW - malonic aciduria
KW - methylmalonic aciduria
UR - http://www.scopus.com/inward/record.url?scp=85135420018&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/brain/awac034
DO - https://doi.org/10.1093/brain/awac034
M3 - Article
C2 - 35104841
SN - 0006-8950
VL - 145
SP - 2602
EP - 2616
JO - Brain
JF - Brain
IS - 7
ER -