Title |
Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation
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Published in |
American Journal of Human Genetics, December 2016
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DOI | 10.1016/j.ajhg.2016.11.011 |
Pubmed ID | |
Authors |
Kezhi Yan, Justine Rousseau, Rebecca Okashah Littlejohn, Courtney Kiss, Anna Lehman, Jill A. Rosenfeld, Constance T.R. Stumpel, Alexander P.A. Stegmann, Laurie Robak, Fernando Scaglia, Thi Tuyet Mai Nguyen, He Fu, Norbert F. Ajeawung, Maria Vittoria Camurri, Lin Li, Alice Gardham, Bianca Panis, Mohammed Almannai, Maria J. Guillen Sacoto, Berivan Baskin, Claudia Ruivenkamp, Fan Xia, Weimin Bi, DDD Study, CAUSES Study, Megan T. Cho, Thomas P. Potjer, Gijs W.E. Santen, Michael J. Parker, Natalie Canham, Margaret McKinnon, Lorraine Potocki, Jennifer J. MacKenzie, Elizabeth R. Roeder, Philippe M. Campeau, Xiang-Jiao Yang |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Italy | 1 | 25% |
Unknown | 3 | 75% |
Demographic breakdown
Type | Count | As % |
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Scientists | 2 | 50% |
Members of the public | 2 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Canada | 1 | 1% |
Unknown | 82 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 18 | 22% |
Researcher | 10 | 12% |
Student > Master | 10 | 12% |
Student > Bachelor | 6 | 7% |
Professor > Associate Professor | 6 | 7% |
Other | 9 | 11% |
Unknown | 24 | 29% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 22 | 27% |
Agricultural and Biological Sciences | 14 | 17% |
Medicine and Dentistry | 8 | 10% |
Psychology | 3 | 4% |
Neuroscience | 3 | 4% |
Other | 5 | 6% |
Unknown | 28 | 34% |