Phenotypic expansion of the BPTF ‐related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies
Kevin E. GlintonAnna HurstKevin M. BowlingIngrid CristianDevon HaynesDusit AdstamongkonkulOskar SchnappaufDavid B. BeckCarole BrewerAditi ParikhDeepali N. ShindeAlan DonaldsonAriel BrautbarSaskia KoeneArie van HaeringenAmélie PitonYline CapriMargherita FurlanElena GardellaRikke S. MøllerIrma van de BeekLinda ZuurbierPhillis LakemanAllan BayatJulián A. Martínez-AgostoRebecca SignerPernille Mathiesen TørringMorten Buch EngelundKaren W. GrippLouise Amlie‐WolfLindsay B. HendersonAlina T. MidroEugeniusz TarasówBeata Stasiewicz‐JarockaDiana Moskal-JasińskaPaul De VosFelix BoschannCorinna StoltenburgOliver PukInger‐Lise MeroKristine LossiusCyril MignotBoris KerenJohanna AcostaIgnacio BriceñoAlberto GómezYaping YangPaweł Stankiewicz
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Abstract Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage‐sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF , including four individuals with inherited changes in BPTF . In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi‐faceted complications due to haploinsufficiency of BPTF .Keywords:
Haploinsufficiency
Microcephaly
Speech delay
Neurodevelopmental disorder
PHD finger
Abstract Neurodevelopmental disorders, including autism spectrum disorder, have complex polygenic etiologies. Single-gene mutations in patients can help define genetic factors and molecular mechanisms underlying neurodevelopmental disorders. Here we describe individuals with monogenic heterozygous microdeletions in ANKS1B , a predicted risk gene for autism and neuropsychiatric diseases. Affected individuals present with a spectrum of neurodevelopmental phenotypes, including autism, attention-deficit hyperactivity disorder, and speech and motor deficits. Neurons generated from patient-derived induced pluripotent stem cells demonstrate loss of the ANKS1B -encoded protein AIDA-1, a brain-specific protein highly enriched at neuronal synapses. A transgenic mouse model of Anks1b haploinsufficiency recapitulates a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction. Identification of the AIDA-1 interactome using quantitative proteomics reveals protein networks involved in synaptic function and the etiology of neurodevelopmental disorders. Our findings formalize a link between the synaptic protein AIDA-1 and a rare, previously undefined genetic disease we term ANKS1B haploinsufficiency syndrome.
Haploinsufficiency
Neurodevelopmental disorder
Interactome
Rett Syndrome
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We report a two-generation family with four females harboring an 8.5Mb heterozygous deletion of 5q15-q21.2 who present with dysmorphic craniofacial features and speech delay. We hypothesize haploinsufficiency of CHD1 to be contributing to the clinical features observed in this family.
Haploinsufficiency
Facial dysmorphism
Speech delay
Gene deletion
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The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethylbenzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and ITC Kd = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.
PHD finger
Histone acetyltransferase
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PHD finger
Transcription
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Binding of the chromatin remodeling complex NoRC to RNA complementary to the rDNA promoter mediates transcriptional repression. TIP5, the largest subunit of NoRC, is involved in recruitment to rDNA by interactions with promoter-bound TTF-I, pRNA, and acetylation of H4K16. TIP5 domains that recognize posttranslational modifications on histones are essential for recruitment of NoRC to chromatin, but how these reader modules recognize site-specific histone tails has remained elusive. Here, we report crystal structures of PHD zinc finger and bromodomains from human TIP5 and BAZ2B in free form and bound to H3 and/or H4 histones. PHD finger functions as an independent structural module in recognizing unmodified H3 histone tails, and the bromodomain prefers H3 and H4 acetylation marks followed by a key basic residue, KacXXR. Further low-resolution analyses of PHD-bromodomain modules provide molecular insights into their trans histone tail recognition, required for nucleosome recruitment and transcriptional repression of the NoRC complex.
PHD finger
Histone code
Histone-modifying enzymes
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Bromodomain-PHD finger protein 1 (BRPF1) is part of the MOZ HAT complex and contains a unique combination of domains typically found in chromatin-associated factors, which include plant homeodomain (PHD) fingers, a bromodomain and a proline-tryptophan-tryptophan-proline (PWWP) domain. Bromodomains are conserved structural motifs generally known to recognize acetylated histones, and the BRPF1 bromodomain preferentially selects for H2AK5ac, H4K12ac and H3K14ac. We solved the X-ray crystal structures of the BRPF1 bromodomain in complex with the H2AK5ac and H4K12ac histone peptides. Site-directed mutagenesis on residues in the BRPF1 bromodomain-binding pocket was carried out to investigate the contribution of specific amino acids on ligand binding. Our results provide critical insights into the molecular mechanism of ligand binding by the BRPF1 bromodomain, and reveal that ordered water molecules are an essential component driving ligand recognition.
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Covalent modifications on histone tails play a key role in determining the outcome of many nuclear processes including transcription, DNA repair, recombination, and replication. In humans, translocation of the monocytic leukemia zinc finger (MOZ) histone acetyltransferase (HAT) complex has been linked to a subtype of acute myeloid leukemia (AML). MOZ forms tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1-associated factor 6 ortholog), and the bromodomain-PHD finger protein. BRPF proteins have been shown to bridge the association of MOZ with ING5 and EAF6. Deletion mapping studies have also revealed that the acetyltransferase domain of MOZ is sufficient for the interaction with BRPF1. BRPF proteins therefore play a key role in assembling and activating MOZ acetyltransferase complexes. BRPF1 contains a unique combination of domains typically found in chromatin-associated factors, including PHD (plant homeodomain) fingers, a bromodomain and a PWWP (Pro-Trp-Trp-Pro) domain. The bromodomain and PWWP domain of BRPF1 help recruit MOZ to distinct sites of active chromatin. Bromodomains are highly conserved motifs generally known to acetylated lysines on the histone tail, but the ligands recognized by BRPF1 bromodomain are currently unknown. In this study we identified the N-terminal histone tail ligands for the BRPF1 bromodomain, characterized the protein-ligand binding affinities and determined the functional importance of these interactions. We also used extensive molecular dynamics simulations to generate structural models of bromodomain-histone ligand complexes, to analyze H-bonding and other interactions, and to calculate the binding free energies. Our results outline the molecular mechanism driving binding specificity of the BRPF1 bromodomain for discrete acetyllysine residues on the N-terminal histone tails. A better understanding of this process will be important for the development of drugs to treat acute myeloid leukemia and other cancers. Grant Funding Source: NIH
Histone acetyltransferase
PHD finger
PCAF
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The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral bioavailability
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Cocrystal
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PHD finger
Histone acetyltransferase
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