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

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.

The BRPF1 bromodomain is a molecular reader of di-acetyllysine

“…Deletion of the mouse BRPF1 gene showed that BRPF1 is crucial for the growth and proliferation of embryonic fibroblasts and hematopoietic progenitors 11 . Also, multiple mutations in the BRPF1 gene have been reported to give rise to neurodevelopmental disorders due to a deficiency in histone H3K23 acetylation, supporting evidence that BRPF1 acts through MOZ and MORF to modulate chromatin modification states 7 .…”

“…Bromodomain-PHD finger protein 1 (BRPF1) is known to play a role in maintaining the expression of genes involved in several developmental processes and hematopoiesis [6][7][8] . The BPRF1 protein is a unique, multivalent chromatin reader which contains an N-terminal plant homeodomain (PHD)-zinc-knuckle-PHD (PZP) module, a bromodomain for acetyllysine recognition, and a C-terminal proline-tryptophan-tryptophan-proline (PWWP) domain 9 .…”

Developmental disorders with intellectual disability driven by chromatin dysregulation: Clinical overlaps and molecular mechanisms

“…81 BRPF1 governs histone H3K23 acetylation through KAT6A and KAT6B as showed by functional assays of BRPF1 pathogenic variants. 81 The signature of aberrant histone 3 acetylation in IDDFB, GPS/BBYYS and MRD32, and also RSTS and FHS and interaction of the epigenetic regulators in some of the syndromes (Table 1) accounts for their clinical commonalities.…”

Say‐Barber‐Biesecker‐Young‐Simpson syndrome and Genitopatellar syndrome: Lumping or splitting?

“…Very interestingly, Yan et al and Mattioli et al identified heterozygous sequence variants in the BRPF1 gene on chromosome 3p25, leading to a phenotype characterized by delayed psychomotor development, intellectual disability, delayed language, and dysmorphic facial features, most notably ptosis/blepharophimosis. Additional features may include poor growth, hypotonia, and seizures (intellectual developmental disorder with dysmorphic facies and ptosis, OMIM #617333).…”

“…However, in their view, molecular evidence confirms that the KAT6B-associated phenotypic spectrum is so broad that some patients cannot be unequivocally classified as SBBYSS or GTPTS, and that typical/not-typical SBBYSS and GTPTS are not simply allelic disorders, rather just 2 ends of a complex phenotypic spectrum referable as "KAT6B spectrum disorders" or "KAT6B-related disorders." Very interestingly, Yan et al28 and Mattioli et al 29 identified heterozygous sequence variants in the BRPF1 gene on chromosome 3p25, leading to a phenotype characterized by delayed psychomotor development, intellectual disability, delayed language, and dysmorphic facial features, most notably ptosis/blepharophimosis. Additional features may include poor growth, hypotonia, and seizures (intellectual developmental disorder with dysmorphic facies and ptosis, OMIM #617333).…”