التفاصيل البيبلوغرافية
| العنوان: |
Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder |
| المؤلفون: |
Undiagnosed Diseases Network |
| المساهمون: |
Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek |
| سنة النشر: |
2022 |
| مصطلحات موضوعية: |
Adolescent, BRCA1 Protein/genetics, Child, Preschool, Chromatin Assembly and Disassembly/genetics, Chromatin/chemistry, Family, Female, Gene Expression Regulation, Germ-Line Mutation, Heterozygote, Histones/genetics, Host Cell Factor C1/genetics, Humans, Infant, Loss of Function Mutation, Male, Mutation, Missense, Neurodevelopmental Disorders/genetics, Proteasome Endopeptidase Complex/genetics, T-Lymphocytes/immunology, Tumor Suppressor Proteins/deficiency, Ubiquitin Thiolesterase/deficiency, Ubiquitin-Protein Ligases/genetics, Ubiquitin/genetics, Ubiquitination, chromatin remodeling, BRCA1, neurodevelopment |
| الوصف: |
Nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic NDD. Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired. In matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| تدمد: |
0002-9297 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/446150 |
| الاتاحة: |
https://dspace.library.uu.nl/handle/1874/446150 |
| Rights: |
info:eu-repo/semantics/ClosedAccess |
| رقم الانضمام: |
edsbas.95170B0C |
| قاعدة البيانات: |
BASE |
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