%0 Journal Article
%T Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation
%A Alexander P.A. Stegmann
%A Alice Gardham
%A Anna Lehman
%A Berivan Baskin
%A Bianca Panis
%A CAUSES Study
%A Claudia Ruivenkamp
%A Constance T.R. Stumpel
%A Courtney Kiss
%A DDD Study
%A Elizabeth R. Roeder
%A Fan Xia
%A Fernando Scaglia
%A Gijs W.E. Santen
%A He Fu
%A Jennifer J. MacKenzie
%A Jill A. Rosenfeld
%A Justine Rousseau
%A Kezhi Yan
%A Laurie Robak
%A Lin Li
%A Lorraine Potocki
%A Margaret McKinnon
%A Maria J. Guillen Sacoto
%A Maria Vittoria Camurri
%A Megan T. Cho
%A Michael J. Parker
%A Mohammed Almannai
%A Natalie Canham
%A Norbert F. Ajeawung
%A Philippe M. Campeau
%A Rebecca Okashah Littlejohn
%A Thi Tuyet Mai Nguyen
%A Thomas P. Potjer
%A Weimin Bi
%J Archive of "American Journal of Human Genetics".
%D 2017
%R 10.1016/j.ajhg.2016.11.011
%X 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
%K developmental disorder
%K intellectual disability
%K epigenetic regulator
%K bromodomain
%K BRPF2
%K PHD finger
%K PWWP domain
%K PZP domain
%K histone acetylation
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223032/