title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
abstract: Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.
authors.affiliation: Rosalind & Morris Goodman Cancer Research Center and Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Kezhi
authors.initials: K
authors.lastname: Yan
authors.affiliation: CHUSJ Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada.
authors.forename: Justine
authors.initials: J
authors.lastname: Rousseau
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 77030, USA.
authors.forename: Rebecca Okashah
authors.initials: RO
authors.lastname: Littlejohn
authors.affiliation: Kingston General Hospital, 76 Stuart Street, Armstrong 4, Kingston, ON K7L 2V7, Canada.
authors.forename: Courtney
authors.initials: C
authors.lastname: Kiss
authors.affiliation: Department of Medical Genetics, University of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Clinical Genetics and School for Oncology & Developmental Biology, Maastricht University Medical Center, Maastricht 6229, the Netherlands.
authors.forename: Constance T R
authors.initials: CTR
authors.lastname: Stumpel
authors.affiliation: Department of Clinical Genetics and School for Oncology & Developmental Biology, Maastricht University Medical Center, Maastricht 6229, the Netherlands.
authors.forename: Alexander P A
authors.initials: APA
authors.lastname: Stegmann
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Robak
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Scaglia
authors.affiliation: CHUSJ Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada.
authors.forename: Thi Tuyet Mai
authors.initials: TTM
authors.lastname: Nguyen
authors.affiliation: CHUSJ Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada.
authors.forename: He
authors.initials: H
authors.lastname: Fu
authors.affiliation: CHUSJ Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Ajeawung
authors.affiliation: CHUSJ Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Camurri
authors.affiliation: Rosalind & Morris Goodman Cancer Research Center and Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: Gardham
authors.affiliation: Department of Pediatrics, Zuyderland Medical Center, Heerlen and Sittard 6419, the Netherlands.
authors.forename: Bianca
authors.initials: B
authors.lastname: Panis
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Almannai
authors.affiliation: GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
authors.forename: Maria J Guillen
authors.initials: MJG
authors.lastname: Sacoto
authors.affiliation: GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
authors.forename: Berivan
authors.initials: B
authors.lastname: Baskin
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden 2300RC, the Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruivenkamp
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.affiliation: Decipher Developmental Disorder Study, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
authors.affiliation: Department of Medical Genetics, University of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
authors.affiliation: GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden 2300RC, the Netherlands.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Potjer
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden 2300RC, the Netherlands.
authors.forename: Gijs W E
authors.initials: GWE
authors.lastname: Santen
authors.affiliation: Sheffield Clinical Genetics Service, OPD2, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
authors.affiliation: North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Canham
authors.affiliation: Department of Medical Genetics, University of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
authors.forename: Margaret
authors.initials: M
authors.lastname: McKinnon
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Potocki
authors.affiliation: Kingston General Hospital, 76 Stuart Street, Armstrong 4, Kingston, ON K7L 2V7, Canada; Division of Clinical Genetics, Department of Pediatrics, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: MacKenzie
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Roeder
authors.affiliation: CHUSJ Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada; Department of Pediatrics, Sainte-Justine Hospital and University of Montreal, QC H3T 1J4, Canada. Electronic address: p.campeau@umontreal.ca.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Campeau
authors.affiliation: Rosalind & Morris Goodman Cancer Research Center and Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University and McGill University Health Center, Montreal, QC H3A 1A3, Canada. Electronic address: xiang-jiao.yang@mcgill.ca.
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins; D002658:Developmental Disabilities / Q000235:genetics; D005145:Face / Q000002:abnormalities; D005260:Female; D051548:Histone Acetyltransferases / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D013577:Syndrome; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D008239:Lysine; D009687:Nuclear Proteins; C086011:BRPF1 protein, human; D000092468:Bromodomain Containing Proteins; C000597967:BRPF1 protein, mouse; C108712:KAT6A protein, human; C487137:KAT6B protein, human
keywords: BRPF2; PHD finger; PWWP domain; PZP domain; bromodomain; developmental disorder; epigenetic regulator; histone acetylation; intellectual disability