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.

• MeSH
• chromatin chemie   imunologie   MeSH
• dítě MeSH
• faktor C1 hostitelské buňky genetika   imunologie   MeSH
• heterozygot MeSH
• histony genetika   imunologie   MeSH
• kojenec MeSH
• lidé MeSH
• missense mutace * MeSH
• mladiství MeSH
• mutace ztráty funkce * MeSH
• nádorové supresorové proteiny nedostatek   genetika   imunologie   MeSH
• neurovývojové poruchy genetika   imunologie   patologie   MeSH
• předškolní dítě MeSH
• proteasomový endopeptidasový komplex genetika   imunologie   MeSH
• protein BRCA1 genetika   imunologie   MeSH
• regulace genové exprese MeSH
• restrukturace chromatinu genetika   imunologie   MeSH
• rodina MeSH
• T-lymfocyty imunologie   patologie   MeSH
• thiolesterasa ubikvitinu nedostatek   genetika   imunologie   MeSH
• ubikvitin genetika   imunologie   MeSH
• ubikvitinace MeSH
• ubikvitinligasy genetika   imunologie   MeSH
• zárodečné mutace * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH