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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

Authors :
Yan, K.Z.
Rousseau, J.
Littlejohn, R.O.
Kiss, C.
Lehman, A.
Rosenfeld, J.A.
Stumpel, C.T.R.
Stegmann, A.P.A.
Robak, L.
Scaglia, F.
Nguyen, T.T.M.
Fu, H.
Ajeawung, N.F.
Camurri, M.V.
Li, L.
Gardham, A.
Panis, B.
Almannai, M.
Sacoto, M.J.G.
Baskin, B.
Ruivenkamp, C.
Xia, F.
Bi, W.
Cho, M.T.
Potjer, T.P.
Santen, G.W.E.
Parker, M.J.
Canham, N.
McKinnon, M.
Potocki, L.
MacKenzie, J.J.
Roeder, E.R.
Campeau, P.M.
Yang, X.J.
DDD Study
CAUSES Study
MUMC+: DA KG Polikliniek (9)
RS: GROW - R4 - Reproductive and Perinatal Medicine
Klinische Genetica
MUMC+: DA KG Lab Centraal Lab (9)
Source :
American Journal of Human Genetics, 100(1), 91-104. Cell Press, American Journal of Human Genetics, 100(1), 91-104
Publication Year :
2017

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. Syrhptoms 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.

Details

Language :
English
ISSN :
00029297
Volume :
100
Issue :
1
Database :
OpenAIRE
Journal :
American Journal of Human Genetics
Accession number :
edsair.doi.dedup.....72412f00f38dd65a2b036a0855313d99
Full Text :
https://doi.org/10.1016/j.ajhg.2016.11.011