Alternative titles; symbols
HGNC Approved Gene Symbol: BRPF1
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38) : 3:9,731,735-9,748,015 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.3 | Intellectual developmental disorder with dysmorphic facies and ptosis | 617333 | Autosomal dominant | 3 |
The BRPF1 gene encodes a multivalent chromatin reader that interacts with and activates histone acetyltransferases, thus playing a role in epigenetic regulation. Specifically, BRPF1 acts in a complex to promote acetylation of histone H3 at lysine 23 (H3K23) (summary by Yan et al., 2017).
Thompson et al. (1994) cloned a cDNA encoding a predicted 1,214-amino acid protein that they designated BR140. The BR140 protein, known also as peregrin, has 6 zinc finger motifs and a bromodomain. Thompson et al. (1994) found that BR140 migrates as a 150-kD protein on SDS-PAGE. Northern blots showed that BR140 is expressed ubiquitously. Western blots and immunohistochemistry revealed that BR140 is expressed at the highest level in testes and spermatogonia, and is localized within nuclei.
Gregorini et al. (1996) noted that BR140 is very similar in structure to 2 other zinc finger genes, AF10 (602409) and AF17 (MLLT6; 600328), and suggested that they form a family of regulatory proteins.
Yan et al. (2017) found histone H3K23 acetylation in various regions of the mouse brain, including the cerebral cortex, hippocampus, olfactory tubercle, and cerebellum. The pattern of H3K23ac distribution was similar to the expression pattern of mouse Brpf1 in the brain.
Gregorini et al. (1996) mapped the BR140 gene to 3p25-p26 by fluorescence in situ hybridization.
BRPF1 serves as a scaffold protein to bridge interaction of the histone acetyltransferases KAT6A (601408) and KAT6B (605880) with ING5 (608525) and MEAF6 (611001). BRPF1 also activates KAT7 (609880). Formation of these complexes leads to acetylation of histone H3 (H3K23) (see, e.g., HIST1H3A, 602810) and epigenetic regulation. The BRPF1 protein contains several different domains: an N-terminal KAT6A- and KAT6B-binding domain, followed by a histone and DNA-binding domain, a nuclear localization signal, an ING5- and MEAF6-binding domain, and finally a C-terminal H3K36me3-binding domain (PWWP). Using cellular immunoprecipitation studies, Yan et al. (2017) demonstrated that BRPF1 acts mainly through KAT6A and KAT6B to control H3K23 acetylation.
In 10 patients from 9 unrelated families with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Yan et al. (2017) identified heterozygous mutations in the BRPF1 gene (see, e.g., 602410.0001-602410.0005). One mutation was a missense mutation, and all the others were nonsense or frameshift mutations leading to C-terminal premature terminations that differed in which structural domains were deleted. Functional assays showed that the resulting BRPF1 variants were pathogenic and impaired acetylation of histone H3 at lysine 23, although they acted through different mechanisms. Mutations that resulted in deletion of domains important for binding to KAT6A, KAT6B and/or ING5 and MEAF6 (see, e.g., 602410.0002 and 602410.0003) were unable to form tetrameric complexes and had reduced ability to stimulate acetyltransferase activity, whereas mutations that occurred distal to these functional domains (see, e.g., 602410.0004) retained the ability to form complexes and had normal acetyltransferase activity, but lacked the PWWP domain, which binds to trimethylated histone H3. The mutations also altered subcellular localization compared to wildtype, again through different mechanisms. The findings suggested that BRPF1 haploinsufficiency, resulting in decreased H3K23 acetylation and deregulation of epigenetic and developmental programs, is the pathogenic mechanism underlying the disorder.
In 5 affected members of a 3-generation family with IDDDFP, Mattioli et al. (2017) identified a heterozygous frameshift mutation in the BRPF1 gene (602410.0006). The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutant protein was able to bind KAT6A, but unable to bind ING5 and MEAF6. Studies of HeLa cells transfected with the mutation showed that the truncated variant failed to stimulate K23 acetylation of histone H3. The mutant protein also showed aberrant intracellular localization. Subsequently, 4 unrelated boys with de novo heterozygous BRPF1 mutations and a phenotype consistent with IDDDFP were identified through the GeneMatcher exchange database (602410.0007-602410.0010). Their phenotype was consistent with IDDDFP. Three of these mutations were truncating mutations, and 1 was a missense mutation. Functional studies of these variants were not performed.
You et al. (2015) generated mice lacking Brpf1 specifically in forebrain. They observed that fewer mice lacking Brpf1 in forebrain were born than expected, suggesting partial prenatal lethality, and that most mutant mice died prior to weaning at day 21. The mutant mice appeared normal at birth and showed normal growth over the first 5 days, but by day 10 they were significantly smaller than control littermates. Surviving mice had decreased appetite and behavioral and neurologic defects. Mutant mice had reduced brain size, altered neocortical development, narrower Ctip2 (606558)-positive layer, and lamination and neuron progenitor production defects. In addition, loss of forebrain Brpf1 reduced Tbr2 (EOMES; 604615), Nr2f1 (132890), and Robo3 (608630), leading to corpus callosum hypoplasia. RT-PCR analysis showed reduced expression of different layer markers, altered expression of transcription factors, and increased expression of several Hox genes (e.g., HOXA7; 142950), which are important for hindbrain development and are normally silenced in neocortex. You et al. (2015) concluded that BRPF1 is important for forebrain development.
You et al. (2015) observed lethality at embryonic day 9.5 in mice lacking Brpf1. The mutant animals showed vascular defects in placenta, yolk sac, and embryo, as well as neural tube closure. Proliferation of embryonic fibroblasts and hemopoietic progenitors was reduced. In addition, Brpf1 loss reduced transcription of Rpl10l and increased expression of Scp3l and Gm773. You et al. (2015) concluded that Brpf1 is important for embryonic development and cell cycle control and noted that its loss causes earlier death and defects in different organs than loss of Brpf2 (BRD1; 604589).
You et al. (2016) found that selective deletion of Brpf1 in mouse blood cells resulted in early lethality due to acute bone marrow failure and aplastic anemia. Bone marrow and liver showed severe deficiency of hemopoietic stem cells and hemopoietic progenitors, along with elevated reactive oxygen species, senescence, and apoptosis. RNA sequencing and quantitative RT-PCR analysis demonstrated decreased expression of multipotency genes, including Slamf1 (603492), Mecom (165215), Hoxa9 (142956), Gfi1 (600871), Egr (128990), and Gata3 (131320). Acetylation of H3K23 also required Brpf1. You et al. (2016) concluded that BRPF1 is essential in hemopoiesis.
Yan et al. (2017) found defective H3K23 acetylation in thymus and spleen protein extracts of transgenic mice with knockdown of Brpf1 specifically in hematopoietic cells. Similar defects were present in dorsal cortex extracts of forebrain-specific Brpf1-knockout mice and protein extracts of epiblast-specific Brpf1-knockout mouse embryos. H3K23 acetylation was not detectable in Brpf1-null mouse embryonic fibroblasts. Heterozygous mutant embryos also showed reduced H3K23 acetylation.
In a male patient (P4) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Yan et al. (2017) identified a heterozygous c.1108C-T transition (c.1108C-T, NM_001003694.1) in the BRPF1 gene, resulting in a pro370-to-ser (P370S) substitution at a highly conserved residue important for binding to the DNA backbone of nucleosomes. The mutation, which was found by exome sequencing, was inherited from the patient's unaffected mother who was mosaic for the mutation. Patient lymphoblastoid cells showed reduced H3K23 acetylation (about 50% of controls). Expression of the mutation into HEK293 cells showed that the P370S mutant was able to form tetrameric complexes with KATA6A, ING5, and MEAF6 similar to wildtype, although it was unable to promote H3K23 acetylation by KAT6A, demonstrating the importance of the DNA-binding loop. The P370S variant showed cytoplasmic distribution different from the wildtype protein, but translocated to the nucleus upon coproduction of KAT6A, ING5, and MEAF6.
In a female patient (P5) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Yan et al. (2017) identified a de novo heterozygous c.1363C-T transition (c.1363C-T, NM_001003694.1) in the BRPF1 gene, resulting in an arg455-to-ter (R455X) substitution just before the nuclear localization signal. The mutation was found by exome sequencing. The truncated protein was predicted to be devoid of the ING5- and MEAF6-interacting domains. Patient fibroblasts showed about 50% decreased H3K23 acetylation compared to controls. However, the mutation did not result in nonsense-mediated mRNA decay. Expression of the mutation into HEK293 cells showed that the R455X mutation failed to promote expression of ING5 and MEAF6, failed to mediate the interaction of KAT6A with ING5 and MEAF6, and had reduced ability to stimulate the acetyltransferase activity of KAT6A, likely due to loss of the ING5 and MEAF6 domains. R455X showed mainly nuclear subcellular localization.
In a female patient (P1) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Yan et al. (2017) identified a de novo heterozygous 2-bp deletion (c.362_363delAG, NM_001003694.1) in the BRPF1 gene, resulting in a frameshift and premature termination (Glu121GlyfsTer2) in the N terminal domain. The mutation was found by exome sequencing. The truncated protein was predicted to be devoid of the ING5- and MEAF6-interacting domains. Expression of the mutation into HEK293 cells showed that the mutant protein was produced at lower levels than wildtype and failed to failed to promote expression of ING5 and MEAF6; it also failed to interact with MEAF6. The mutant protein showed uniform cytoplasmic distribution, but moved to the nucleus in the presence of KAT6A, ING5, and MEAF6.
In a female patient (P8) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Yan et al. (2017) identified a de novo heterozygous c.2497C-T transition (c.2497C-T, NM_001003694.1) in the BRPF1 gene, resulting in an arg833-to-ter (R833X) substitution. The mutation was found by exome sequencing. The mutation occurred distal to the binding sites with other acetyltransferase proteins, but lacked the PWWP domain, which binds to trimethylated histone H3. Expression of the mutation into HEK293 cells showed that the mutant protein retained its ability to form tetrameric complexes with KAT6A, KAT6B, ING5, and MEAF6, and was as active as wildtype in stimulating the acetyltransferase activity of KAT6A. The R833X protein formed large aggregates in the cytoplasm, but became nuclear upon coproduction of KAT6A, ING5, and MEAF6.
In a female patient (P10) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Yan et al. (2017) identified a de novo heterozygous c.3298C-T transition (c.3298C-T, NM_001003694.1) in the BRPF1 gene, resulting in an arg1100-to-ter (R1100X) substitution. The mutation was found by exome sequencing. The mutation occurred distal to the binding sites with other acetyltransferase proteins, but occurred within the PWWP domain, which binds to trimethylated histone H3. Expression of the mutation into HEK293 cells showed that the mutant protein retained its ability to form tetrameric complexes with KAT6A, KAT6B, ING5, and MEAF6, and was as active as wildtype in stimulating the acetyltransferase activity of KAT6A.
In 5 affected members of a 3-generation family (family A) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Mattioli et al. (2017) identified a heterozygous 2-bp deletion (c.1052_1053del, NM_001003694.1) in the BRPF1 gene, resulting in a frameshift and premature termination (Val351GlyfsTer8). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against public databases and was not found in the ExAC database. Analysis of patient cells showed that the mutated transcript partially escaped nonsense-mediated mRNA decay. The truncated protein was predicted to lack the ING5- and MEAF6-binding domains, as well as the PWWP domain. In vitro functional expression studies in HEK293 cells showed that the mutant protein was able to bind KAT6A, but unable to bind ING5 and MEAF6. Patient fibroblasts showed no significant differences in H3 acetylation levels compared to controls, and only a slight and nonsignificant decrease in the acetylation of H3K23 compared to controls. However, studies of HeLa cells transfected with the mutation showed that the truncated variant failed to stimulate K23 acetylation of histone H3. The mutant protein also showed aberrant intracellular localization, with more uniform cytoplasmic and nuclear distribution compared to wildtype.
In a 10-year-old boy (individual 9) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Mattioli et al. (2017) reported a de novo heterozygous c.2982C-G transversion (c.2982C-G, NM_001003694.1) in the BRPF1 gene, resulting in a tyr994-to-ter (Y994X) substitution. The truncated protein was predicted to lack the PWWP domain. Functional studies of the variant and studies of patient cells were not performed. The patient was identified through the GeneMatcher exchange database, and the mutation was found by whole-exome sequencing.
In a 3-year-old boy (individual 10) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Mattioli et al. (2017) reported a de novo heterozygous 1-bp deletion (c.567delT, NM_001003694.1) in the BRPF1 gene, resulting in a frameshift and premature termination (Asp190MetfsTer24). The truncated protein was predicted to lack at least part of the interaction domain with KAT6A and KAT6B, and all of the interaction domain with ING5 and MEAF6. Functional studies of the variant and studies of patient cells were not performed. The patient was identified through the GeneMatcher exchange database, and the mutation was found by whole-exome sequencing.
In a 12-year-old boy (individual 11) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Mattioli et al. (2017) reported a heterozygous 1-bp duplication (c.104dupA, NM_001003694.1) in the BRPF1 gene, resulting in a frameshift and premature termination (Tyr35Ter) in the N terminus. The truncated protein was predicted to lack the interaction domain with KAT6A and KAT6B as well as the interaction domain with ING5 and MEAF6. Functional studies of the variant and studies of patient cells were not performed. The patient was identified through the GeneMatcher exchange database, and the mutation was found by whole-exome sequencing. The patient was adopted; parental DNA was not available to test for de novo status.
In a 3.9-year-old boy (individual 12) with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP; 617333), Mattioli et al. (2017) reported a de novo heterozygous c.1165T-C transition (c.1165T-C, NM_001003694.1) in the BRPF1 gene, resulting in a cys389-to-arg (C389R) substitution at a conserved residue in the second PHD domain. Functional studies of the variant and studies of patient cells were not performed. The patient was identified through the GeneMatcher exchange database, and the mutation was found by whole-exome sequencing.
Gregorini, A., Sahin, F. I., Lillington, D. M., Meerabux, J., Saha, V., McCullagh, P., Bocci, M., Menevse, S., Papa, S., Young, B. D. Gene BR140, which is related to AF10 and AF17, maps to chromosome band 3p25. Genes Chromosomes Cancer 17: 269-272, 1996. [PubMed: 8946209] [Full Text: https://doi.org/10.1002/1098-2264(199612)17:4<269::aid-gcc2870170402>3.0.co;2-a]
Mattioli, F., Schaefer, E., Magee, A., Mark, P., Mancini, G. M., Dieterich, K., Von Allmen, G., Alders, M., Coutton, C., van Slegtenhorst, M., Vieville, G., Engelen, M., Cobben, J. M., Juusola, J., Pujol, A., Mandel, J.-L., Piton, A. Mutations in histone acetylase modifier BRPF1 cause an autosomal-dominant form of intellectual disability with associated ptosis. Am. J. Hum. Genet. 100: 105-116, 2017. [PubMed: 27939639] [Full Text: https://doi.org/10.1016/j.ajhg.2016.11.010]
Thompson, K. A., Wang, B., Argraves, W. S., Giancotti, F. G., Schranck, D. P., Ruoslahti, E. BR140, a novel zinc-finger protein with homology to the TAF250 subunit of TFIID. Biochem. Biophys. Res. Commun. 198: 1143-1152, 1994. [PubMed: 7906940] [Full Text: https://doi.org/10.1006/bbrc.1994.1162]
Yan, K., 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., and 24 others. Mutations in the chromatin regulator gene BRPF1 cause syndromic intellectual disability and deficient histone acetylation. Am. J. Hum. Genet. 100: 91-104, 2017. [PubMed: 27939640] [Full Text: https://doi.org/10.1016/j.ajhg.2016.11.011]
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You, L., Yan, K., Zou, J., Zhao, H., Bertos, N. R., Park, M., Wang, E., Yang, X.-J. The chromatin regulator Brpf1 regulates embryo development and cell proliferation. J. Biol. Chem. 290: 11349-11364, 2015. [PubMed: 25773539] [Full Text: https://doi.org/10.1074/jbc.M115.643189]
You, L., Zou, J., Zhao, H., Bertos, N. R., Park, M., Wang, E., Yang, X.-J. Deficiency of the chromatin regulator Brpf1 causes abnormal brain development. J. Biol. Chem. 290: 7114-7129, 2015. [PubMed: 25568313] [Full Text: https://doi.org/10.1074/jbc.M114.635250]