ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences.
RNA-sequencing
ZBTB11
chromatin immunoprecipitation (ChIP)-sequencing
malonic aciduria
methylmalonic aciduria
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
29 07 2022
29 07 2022
Historique:
received:
31
03
2021
revised:
07
12
2021
accepted:
20
12
2021
pubmed:
2
2
2022
medline:
3
8
2022
entrez:
1
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35104841
pii: 6519384
doi: 10.1093/brain/awac034
pmc: PMC9337812
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2602-2616Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
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