2. Academic Validation
  3. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

  • Am J Hum Genet. 2017 Jan 5;100(1):91-104. doi: 10.1016/j.ajhg.2016.11.011.
Kezhi Yan 1,  Justine Rousseau 2,  Rebecca Okashah Littlejohn 3,  Courtney Kiss 4,  Anna Lehman 5,  Jill A Rosenfeld 6,  Constance T R Stumpel 7,  Alexander P A Stegmann 7,  Laurie Robak 6,  Fernando Scaglia 6,  Thi Tuyet Mai Nguyen 2,  He Fu 2,  Norbert F Ajeawung 2,  Maria Vittoria Camurri 2,  Lin Li 1,  Alice Gardham 8,  Bianca Panis 9,  Mohammed Almannai 6,  Maria J Guillen Sacoto 10,  Berivan Baskin 10,  Claudia Ruivenkamp 11,  Fan Xia 6,  Weimin Bi 6,  DDD Study 12,  CAUSES Study 5,  Megan T Cho 10,  Thomas P Potjer 11,  Gijs W E Santen 11,  Michael J Parker 13,  Natalie Canham 8,  Margaret McKinnon 5,  Lorraine Potocki 6,  Jennifer J MacKenzie 14,  Elizabeth R Roeder 15,  Philippe M Campeau 16,  Xiang-Jiao Yang 17
Affiliations

Affiliations

  • 1 Rosalind & Morris Goodman Cancer Research Center and Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada.
  • 2 CHUSJ Research Center, CHU Sainte-Justine, Montreal, QC H3T 1J4, Canada.
  • 3 Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 77030, USA.
  • 4 Kingston General Hospital, 76 Stuart Street, Armstrong 4, Kingston, ON K7L 2V7, Canada.
  • 5 Department of Medical Genetics, University of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
  • 6 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 7 Department of Clinical Genetics and School for Oncology & Developmental Biology, Maastricht University Medical Center, Maastricht 6229, the Netherlands.
  • 8 North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Northwick Park Hospital, Watford Road, Harrow HA1 3UJ, UK.
  • 9 Department of Pediatrics, Zuyderland Medical Center, Heerlen and Sittard 6419, the Netherlands.
  • 10 GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
  • 11 Department of Clinical Genetics, Leiden University Medical Center, Leiden 2300RC, the Netherlands.
  • 12 Decipher Developmental Disorder Study, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
  • 13 Sheffield Clinical Genetics Service, OPD2, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK.
  • 14 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.
  • 15 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.
  • 16 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.
  • 17 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.
PMID: 27939640 DOI: 10.1016/j.ajhg.2016.11.011
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.

Keywords

BRPF2; PHD finger; PWWP domain; PZP domain; bromodomain; developmental disorder; epigenetic regulator; histone acetylation; intellectual disability.

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