Academic Journal
ZBTB11 dysfunction: Spectrum of brain abnormalities, biochemical signature and cellular consequences ; ENEngelskEnglishZBTB11 dysfunction: Spectrum of brain abnormalities, biochemical signature and cellular consequences
| العنوان: | ZBTB11 dysfunction: Spectrum of brain abnormalities, biochemical signature and cellular consequences ; ENEngelskEnglishZBTB11 dysfunction: Spectrum of brain abnormalities, biochemical signature and cellular consequences |
|---|---|
| المؤلفون: | Sumathipala, Dulika Sanjeewani, Strømme, Petter, Fattahi, Zohreh, Lüders, Torben, Sheng, Ying, Kahrizi, Kimia, Holm, Ingunn, 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 |
| المصدر: | 0006-8950. |
| سنة النشر: | 2022 |
| المجموعة: | Universitet i Oslo: Digitale utgivelser ved UiO (DUO) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | HSØ/276940; Sumathipala, Dulika Sanjeewani Strømme, Petter Fattahi, Zohreh Lüders, Torben Sheng, Ying Kahrizi, Kimia Holm, Ingunn 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 . ZBTB11 dysfunction: Spectrum of brain abnormalities, biochemical signature and cellular consequences. Brain. 2022, 145(7), 2602-2616; http://hdl.handle.net/10852/98974; 2064175; info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Brain&rft.volume=145&rft.spage=2602&rft.date=2022; Brain; 145; 2602; 2616; https://doi.org/10.1093/brain/awac034 |
| DOI: | 10.1093/brain/awac034 |
| الاتاحة: | http://hdl.handle.net/10852/98974 https://doi.org/10.1093/brain/awac034 |
| Rights: | Attribution-NonCommercial 4.0 International ; https://creativecommons.org/licenses/by-nc/4.0/ |
| رقم الانضمام: | edsbas.52EDF1E9 |
| قاعدة البيانات: | BASE |
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