title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
abstract: De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first single gene disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS.
authors.affiliation: Department of Human Genetics.
authors.forename: Anshika
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Department of Human Genetics.
authors.forename: K C
authors.initials: KC
authors.lastname: Ritesh
authors.affiliation: Department of Human Genetics.
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Tsan
authors.affiliation: Department of Human Genetics.
authors.forename: Rosy
authors.initials: R
authors.lastname: Liao
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, Departments of Urology, Computational Medicine and Bioinformatics, and.
authors.forename: Fengyun
authors.initials: F
authors.lastname: Su
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, Departments of Urology, Computational Medicine and Bioinformatics, and.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hannibal
authors.affiliation: Department of Human Genetics, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Keegan
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, Departments of Urology, Computational Medicine and Bioinformatics, and.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Department of Human Genetics, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
authors.affiliation: Department of Human Genetics, sbielas@umich.edu.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Bielas
mesh_terms: D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005183:Failure to Thrive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006579:Heterozygote; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007805:Language Development Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D061251:Primary Cell Culture; D011485:Protein Binding; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D012097:Repressor Proteins
chemical_list: D006657:Histones; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase; C494423:ASXL3 protein, human; D012097:Repressor Proteins; C400134:BAP1 protein, human