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Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

ABSTRACT: Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

SUBMITTER: Tessadori F

PROVIDER: S-EPMC9069069 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Tessadori Federico F Duran Karen K Knapp Karen K Fellner Matthias M Smithson Sarah S Beleza Meireles Ana A Elting Mariet W MW Waisfisz Quinten Q O'Donnell-Luria Anne A Nowak Catherine C Douglas Jessica J Ronan Anne A Brunet Theresa T Kotzaeridou Urania U Svihovec Shayna S Saenz Margarita S MS Thiffault Isabelle I Del Viso Florencia F Devine Patrick P Rego Shannon S Tenney Jessica J van Haeringen Arie A Ruivenkamp Claudia A L CAL Koene Saskia S Robertson Stephen P SP Deshpande Charulata C Pfundt Rolph R Verbeek Nienke N van de Kamp Jiddeke M JM Weiss Janneke M M JMM Ruiz Anna A Gabau Elisabeth E Banne Ehud E Pepler Alexander A Bottani Armand A Laurent Sacha S Guipponi Michel M Bijlsma Emilia E Bruel Ange-Line AL Sorlin Arthur A Willis Mary M Powis Zoe Z Smol Thomas T Vincent-Delorme Catherine C Baralle Diana D Colin Estelle E Revencu Nicole N Calpena Eduardo E Wilkie Andrew O M AOM Chopra Maya M Cormier-Daire Valerie V Keren Boris B Afenjar Alexandra A Niceta Marcello M Terracciano Alessandra A Specchio Nicola N Tartaglia Marco M Rio Marlene M Barcia Giulia G Rondeau Sophie S Colson Cindy C Bakkers Jeroen J Mace Peter D PD Bicknell Louise S LS van Haaften Gijs G

American journal of human genetics 20220223 4

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, ...[more]

PMID: 35202563

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Project description:Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for various developmental and physiological functions. Although its dysfunction is increasingly recognized in abnormal phenotypes, to our knowledge, there have been no established reports of human diseases directly linked to HDAC3 dysfunction. Using trio exome sequencing and extensive phenotypic analysis, we correlated heterozygous de novo variants in HDAC3 with a neurodevelopmental disorder having variable clinical presentations, frequently associated with intellectual disability, developmental delay, epilepsy, and musculoskeletal abnormalities. In a cohort of six individuals, we identified missense variants in HDAC3 (c.277G>A [p.Asp93Asn], c.328G>A [p.Ala110Thr], c.601C>T [p.Pro201Ser], c. 797T>C [p.Leu266Ser], c.799G>A [p.Gly267Ser], and c.1075C>T [p.Arg359Cys]), all located in evolutionarily conserved sites and confirmed as de novo. Experimental studies identified defective deacetylation activity in the p.Asp93Asn, p.Pro201Ser, p.Leu266Ser, and p.Gly267Ser variants, positioned near the enzymatic pocket. In addition, proteomic analysis employing co-immunoprecipitation revealed that the disrupted interactions with molecules involved in the CoREST and NCoR complexes, particularly in the p.Ala110Thr variant, consist of a central pathogenic mechanism. Moreover, immunofluorescence analysis showed diminished nuclear to cytoplasmic fluorescence ratio in the p.Ala110Thr, p.Gly267Ser, and p.Arg359Cys variants, indicating impaired nuclear localization. Taken together, our study highlights that de novo missense variants in HDAC3 are associated with a broad spectrum of neurodevelopmental disorders, which emphasizes the complex role of HDAC3 in histone deacetylase activity, multi-protein complex interactions, and nuclear localization for proper physiological functions. These insights open new avenues for understanding the molecular mechanisms of HDAC3-related disorders and may inform future therapeutic strategies.

Dataset Information

Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Publications

Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

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