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Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

S. Küry, F. Ebstein, A. Mollé, T. Besnard, MK. Lee, V. Vignard, T. Hery, M. Nizon, GMS. Mancini, JC. Giltay, B. Cogné, K. McWalter, W. Deb, H. Mor-Shaked, H. Li, RE. Schnur, IM. Wentzensen, AS. Denommé-Pichon, C. Fourgeux, FW. Verheijen, E....

American journal of human genetics. 2022 ; 109 (2) : 361-372. [pub] 20220119

Am J Hum Genet
ISSN 1537-6605
Medvik
Zdroj

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem

Perzistentní odkaz https://www.medvik.cz/link/bmc22011065

Grantová podpora
U01 HG007672 NHGRI NIH HHS - United States

Online Plný text

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PubMed 35051358
DOI 10.1016/j.ajhg.2021.12.011
Knihovny.cz E-zdroje

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.

Baylor Genetics Laboratory Houston TX 77021 USA

Center for Genetic Medicine Research Rare Disease Institute Children's National Medical Center Washington DC 20010 USA

CHRU Brest Génétique Médicale 29609 Brest France

CHU Angers Département de Biochimie et Génétique 49933 Angers Cedex 9 France

CHU Poitiers Service de Génétique BP577 86021 Poitiers France

CNRS UMR 6290 IGDR Institut de Génétique et développement de Rennes Université de Rennes 2 Avenue du Professeur Léon Bernard 35043 Rennes France

Department of Biology and Medical Genetics 2nd School of Medicine Charles University Prague and Faculty Hospital Motol 5 Úvalu 84 150 06 Prague 5 Czech Republic

Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam 3015 Rotterdam the Netherlands

Department of Genetics Hadassah Hebrew University Medical Center Jerusalem 9112001 Israel

Department of Genetics University of Alabama at Birmingham Birmingham AL 35233 USA

Department of Human Genetics and Pediatrics School of Medicine Emory University Atlanta GA 30322 USA

Department of Human Genetics Emory University School of Medicine Atlanta GA 30322 USA

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX 77030 USA

Department of Pediatrics Stanford University School of Medicine Stanford CA 94304 USA

Department of Pediatrics University of Tennessee College of Medicine Chattanooga TN 37403 USA

Division Laboratories Pharmacy and Biomedical Genetics University Medical Center Utrecht PO Box 85090 3508 Utrecht the Netherlands

Division of Medical Genetics Department of Pediatrics Duke University Medical Center Durham NC 27710 USA

EA 3808 Université Poitiers 86034 Poitiers France

GeneDx 207 Perry Parkway Gaithersburg MD 20877 USA

Genomic Medicine Columbia University New York NY 10032 USA

INSERM U934 CNRS UMR 3215 75248 Paris France

Institut Curie Paris Sciences et Lettres Research University 75248 Paris France

Institut Curie PSL Research University INSERM U830 DNA Repair and Uveal Melanoma Equipe Labellisée Par la Ligue Nationale Contre le Cancer 75248 Paris France

Institut Curie SIREDO 75005 Paris France

Institut für Medizinische Biochemie und Molekularbiologie Universitätsmedizin Greifswald 17475 Greifswald Germany

Office of the Clinical Director National Human Genome Research Institute National Institutes of Health 10 Center Drive 10 10C103 MSC 1851 Bethesda MD 20892 USA

PANDA 5887 Glenridge Drive Suite 140 Atlanta GA 30328 USA

Service de Génétique Centre Hospitalier Régional Universitaire 37044 Tours France

Service de Génétique Clinique Centre Référence Déficiences Intellectuelles de causes rares Centre de Référence Anomalies du Développement CLAD Ouest ERN ITHACA CHU Rennes 35203 Rennes France

Service de Génétique Médicale CHU Nantes 44093 Nantes France

UMR 1253 iBrain Université de Tours INSERM 37032 Tours France

UMR CNRS 6214 INSERM 1083 Université d'Angers 49933 Angers Cedex 9 France

Université de Nantes CHU Nantes CNRS INSERM l'Institut du Thorax 44007 Nantes France

Université de Nantes CHU Nantes Inserm Centre de Recherche en Transplantation et Immunologie UMR 1064 ITUN 44000 Nantes France

Citace poskytuje Crossref.org

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Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder

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