De novodominantASXL3mutations 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.

Bainbridge–Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition

“…9 Until recently, only nine different de novo truncating ASXL3 germline variants have been identified in individuals with the clinical diagnosis of BRPS. 2,[10][11][12] Thus, available information about BRPS is still limited. In addition, three different LoF variants have been identified in a large autism cohort.…”

“…Patient 1 by Srivastava et al 11 patient 1 was not able to sit, crawl or stand at age 6 years, patient 2 was not able to walk at age 4 years and patient 3 was unable to roll over or sit upright at age 13 months. 11 The patient published by Hori et al 12 was able to sit without support at age 2 years and to stand holding on to things at age 3 years. Speech development was also impaired in all 12 patients in whom this information was available.…”

“…Mutational spectrum ASXL3 shares a common domain architecture with its family members ASXL1 and ASXL2, and although sequence variants in both, the ASXL3 and ASXL1 genes cause disorders with DD and ID, ASXL3 gene Notably, six of the nine previously published variants as well as two of the newly identified variants (patients 1 and 2) are located in exon 11; 2 mutations described by Srivastava et al, 11 and 4 of the 6 mutations newly described in this study (patients 3-6) are located in the last exon 12.…”

Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients withde novo, heterozygous, loss-of-function mutations inASXL3and review of published literature

“…Srivastava et al 9 showed that additional sex combs like 3 (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. The authors observed a significant increase in H2AK119Ub1 in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination.…”

Retraso global del desarrollo y microcefalia posnatal: síndrome de Bainbridge-Ropers con una nueva variante de novo en ASXL3

“…El fenotipo sutil y variable deriva en que el diagnóstico se establece con la secuenciación completa del genoma o del exoma 3,[8][9][10][11] . Las características clíni-cas comunes, retraso psicomotor grave, dismorfias faciales, falla del crecimiento y dificultades para la alimentación se confunden con otros síndromes como el síndrome de Bohring-Opitz (BOS, MIM # 605039) (tabla 1) 12,13 .…”