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.

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

CHU Poitiers Service de Génétique BP577 86021 Poitiers France; EA 3808 Université Poitiers 86034 Poitiers 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; Baylor Genetics Laboratory Houston TX 77021 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

GeneDx 207 Perry Parkway Gaithersburg MD 20877 USA

Genomic Medicine Columbia University New York NY 10032 USA

Institut Curie Paris Sciences et Lettres Research University 75248 Paris France; INSERM U934 CNRS UMR 3215 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; UMR 1253 iBrain Université de Tours INSERM 37032 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; CNRS UMR 6290 IGDR Institut de Génétique et développement de Rennes Université de Rennes 2 Avenue du Professeur Léon Bernard 35043 Rennes France

Service de Génétique Médicale CHU Nantes 44093 Nantes France

Service de Génétique Médicale CHU Nantes 44093 Nantes France; Université de Nantes CHU Nantes CNRS INSERM l'Institut du Thorax 44007 Nantes 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

Zobrazit více v PubMed

Chiti F., Dobson C.M. Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. Annu. Rev. Biochem. 2017;86:27–68. PubMed

Franić D., Zubčić K., Boban M. Nuclear Ubiquitin-Proteasome Pathways in Proteostasis Maintenance. Biomolecules. 2021;11:54. PubMed PMC

Samant R.S., Livingston C.M., Sontag E.M., Frydman J. Distinct proteostasis circuits cooperate in nuclear and cytoplasmic protein quality control. Nature. 2018;563:407–411. PubMed PMC

Pickart C.M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 2001;70:503–533. PubMed

Pickart C.M., Eddins M.J. Ubiquitin: structures, functions, mechanisms. Biochim. Biophys. Acta. 2004;1695:55–72. PubMed

Meyer-Schwesinger C. The ubiquitin-proteasome system in kidney physiology and disease. Nat. Rev. Nephrol. 2019;15:393–411. PubMed

Szczepanski A.P., Wang L. Emerging multifaceted roles of BAP1 complexes in biological processes. Cell Death Discov. 2021;7:20. PubMed PMC

Masclef L., Ahmed O., Estavoyer B., Larrivée B., Labrecque N., Nijnik A., Affar E.B. Roles and mechanisms of BAP1 deubiquitinase in tumor suppression. Cell Death Differ. 2021;28:606–625. PubMed PMC

Jensen D.E., Rauscher F.J., 3rd Defining biochemical functions for the BRCA1 tumor suppressor protein: analysis of the BRCA1 binding protein BAP1. Cancer Lett. 1999;143(Suppl 1):S13–S17. PubMed

Louie B.H., Kurzrock R. BAP1: Not just a BRCA1-associated protein. Cancer Treat. Rev. 2020;90:102091. PubMed PMC

Popova T., Hebert L., Jacquemin V., Gad S., Caux-Moncoutier V., Dubois-d’Enghien C., Richaudeau B., Renaudin X., Sellers J., Nicolas A., et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am. J. Hum. Genet. 2013;92:974–980. PubMed PMC

Srivastava A., Ritesh K.C., Tsan Y.C., Liao R., Su F., Cao X., Hannibal M.C., Keegan C.E., Chinnaiyan A.M., Martin D.M., Bielas S.L. De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. Hum. Mol. Genet. 2016;25:597–608. PubMed PMC

Campagne A., Lee M.K., Zielinski D., Michaud A., Le Corre S., Dingli F., Chen H., Shahidian L.Z., Vassilev I., Servant N., et al. BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation. Nat. Commun. 2019;10:348. PubMed PMC

Scheuermann J.C., de Ayala Alonso A.G., Oktaba K., Ly-Hartig N., McGinty R.K., Fraterman S., Wilm M., Muir T.W., Müller J. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature. 2010;465:243–247. PubMed PMC

Bononi A., Giorgi C., Patergnani S., Larson D., Verbruggen K., Tanji M., Pellegrini L., Signorato V., Olivetto F., Pastorino S., et al. BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature. 2017;546:549–553. PubMed PMC

Zhao W., Steinfeld J.B., Liang F., Chen X., Maranon D.G., Jian Ma C., Kwon Y., Rao T., Wang W., Sheng C., et al. BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature. 2017;550:360–365. PubMed PMC

Ladanyi M., Zauderer M.G., Krug L.M., Ito T., McMillan R., Bott M., Giancotti F. New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. Clin. Cancer Res. 2012;18:4485–4490. PubMed PMC

Liao L., Testa J.R., Yang H. The roles of chromatin-remodelers and epigenetic modifiers in kidney cancer. Cancer Genet. 2015;208:206–214. PubMed PMC

Sobreira N., Schiettecatte F., Valle D., Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum. Mutat. 2015;36:928–930. PubMed PMC

Berger S.I., Ciccone C., Simon K.L., Malicdan M.C., Vilboux T., Billington C., Fischer R., Introne W.J., Gropman A., Blancato J.K., et al. Exome analysis of Smith-Magenis-like syndrome cohort identifies de novo likely pathogenic variants. Hum. Genet. 2017;136:409–420. PubMed PMC

Baux D., Van Goethem C., Ardouin O., Guignard T., Bergougnoux A., Koenig M., Roux A.F. MobiDetails: online DNA variants interpretation. Eur. J. Hum. Genet. 2021;29:356–360. PubMed PMC

Karczewski K.J., Francioli L.C., Tiao G., Cummings B.B., Alföldi J., Wang Q., Collins R.L., Laricchia K.M., Ganna A., Birnbaum D.P., et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–443. PubMed PMC

Traynelis J., Silk M., Wang Q., Berkovic S.F., Liu L., Ascher D.B., Balding D.J., Petrovski S. Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation. Genome Res. 2017;27:1715–1729. PubMed PMC

Jensen D.E., Proctor M., Marquis S.T., Gardner H.P., Ha S.I., Chodosh L.A., Ishov A.M., Tommerup N., Vissing H., Sekido Y., et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998;16:1097–1112. PubMed

Santiago-Sim T., Burrage L.C., Ebstein F., Tokita M.J., Miller M., Bi W., Braxton A.A., Rosenfeld J.A., Shahrour M., Lehmann A., et al. Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features. Am. J. Hum. Genet. 2017;100:676–688. PubMed PMC

Garret P., Ebstein F., Delplancq G., Dozieres-Puyravel B., Boughalem A., Auvin S., Duffourd Y., Klafack S., Zieba B.A., Mahmoudi S., et al. Report of the first patient with a homozygous OTUD7A variant responsible for epileptic encephalopathy and related proteasome dysfunction. Clin. Genet. 2020;97:567–575. PubMed

del Rosario R.C., Poschmann J., Rouam S.L., Png E., Khor C.C., Hibberd M.L., Prabhakar S. Sensitive detection of chromatin-altering polymorphisms reveals autoimmune disease mechanisms. Nat. Methods. 2015;12:458–464. PubMed

Sun W., Poschmann J., Cruz-Herrera Del Rosario R., Parikshak N.N., Hajan H.S., Kumar V., Ramasamy R., Belgard T.G., Elanggovan B., Wong C.C.Y., et al. Histone Acetylome-wide Association Study of Autism Spectrum Disorder. Cell. 2016;167:1385–1397.e11. PubMed

Marzi S.J., Leung S.K., Ribarska T., Hannon E., Smith A.R., Pishva E., Poschmann J., Moore K., Troakes C., Al-Sarraj S., et al. A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat. Neurosci. 2018;21:1618–1627. PubMed

Latypova X., Vincent M., Mollé A., Adebambo O.A., Fourgeux C., Khan T.N., Caro A., Rosello M., Orellana C., Niyazov D., et al. Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder. Am. J. Hum. Genet. 2021;108:929–941. PubMed PMC

McLean C.Y., Bristor D., Hiller M., Clarke S.L., Schaar B.T., Lowe C.B., Wenger A.M., Bejerano G. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 2010;28:495–501. PubMed PMC

Ge Z., Leighton J.S., Wang Y., Peng X., Chen Z., Chen H., Sun Y., Yao F., Li J., Zhang H., et al. Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types. Cell Rep. 2018;23:213–226.e3. PubMed PMC

Hirosawa T., Ishida M., Ishii K., Kanehara K., Kudo K., Ohnuma S., Kamei T., Motoi F., Naitoh T., Selaru F.M., Unno M. Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer. PLoS ONE. 2018;13:e0206643. PubMed PMC

Škrott Z., Cvek B. Linking the activity of bortezomib in multiple myeloma and autoimmune diseases. Crit. Rev. Oncol. Hematol. 2014;92:61–70. PubMed

Shashi V., Pena L.D.M., Kim K., Burton B., Hempel M., Schoch K., Walkiewicz M., McLaughlin H.M., Cho M., Stong N., et al. De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. Am. J. Hum. Genet. 2016;99:991–999. PubMed PMC

Qi H., Dong C., Chung W.K., Wang K., Shen Y. Deep Genetic Connection Between Cancer and Developmental Disorders. Hum. Mutat. 2016;37:1042–1050. PubMed PMC

Errichiello E., Mustafa N., Vetro A., Notarangelo L.D., de Jonge H., Rinaldi B., Vergani D., Giglio S.R., Morbini P., Zuffardi O. SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type. J. Pathol. 2017;243:9–15. PubMed PMC