Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.
Am J Hum Genet
; 109(2): 361-372, 2022 02 03.
Article
em En
| MEDLINE
| ID: mdl-35051358
ABSTRACT
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.
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Texto completo:
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Bases de dados:
MEDLINE
Assunto principal:
Mutação em Linhagem Germinativa
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Proteína BRCA1
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Mutação de Sentido Incorreto
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Proteínas Supressoras de Tumor
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Ubiquitina Tiolesterase
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Transtornos do Neurodesenvolvimento
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Mutação com Perda de Função
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2022
Tipo de documento:
Article