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Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features.


ABSTRACT: Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two missense variants (eight de novo and two of unknown origin) in BPTF on 17q24.2. The BPTF variants were found in unrelated individuals aged between 2.1 and 13 years, who manifest variable degrees of developmental delay/intellectual disability (10/10), speech delay (10/10), postnatal microcephaly (7/9), and dysmorphic features (9/10). Using CRISPR-Cas9 genome editing of bptf in zebrafish to induce a loss of gene function, we observed a significant reduction in head size of F0 mutants compared to control larvae. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and phospho-histone H3 (PH3) staining to assess apoptosis and cell proliferation, respectively, showed a significant increase in cell death in F0 mutants compared to controls. Additionally, we observed a substantial increase of the ceratohyal angle of the craniofacial skeleton in bptf F0 mutants, indicating abnormal craniofacial patterning. Taken together, our data demonstrate the pathogenic role of BPTF haploinsufficiency in syndromic neurodevelopmental anomalies and extend the clinical spectrum of human disorders caused by ablation of chromatin remodeling complexes.

SUBMITTER: Stankiewicz P 

PROVIDER: S-EPMC5630163 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Haploinsufficiency of the Chromatin Remodeler BPTF Causes Syndromic Developmental and Speech Delay, Postnatal Microcephaly, and Dysmorphic Features.

Stankiewicz Paweł P   Khan Tahir N TN   Szafranski Przemyslaw P   Slattery Leah L   Streff Haley H   Vetrini Francesco F   Bernstein Jonathan A JA   Brown Chester W CW   Rosenfeld Jill A JA   Rednam Surya S   Scollon Sarah S   Bergstrom Katie L KL   Parsons Donald W DW   Plon Sharon E SE   Vieira Marta W MW   Quaio Caio R D C CRDC   Baratela Wagner A R WAR   Acosta Guio Johanna C JC   Armstrong Ruth R   Mehta Sarju G SG   Rump Patrick P   Pfundt Rolph R   Lewandowski Raymond R   Fernandes Erica M EM   Shinde Deepali N DN   Tang Sha S   Hoyer Juliane J   Zweier Christiane C   Reis André A   Reis André A   Bacino Carlos A CA   Xiao Rui R   Breman Amy M AM   Smith Janice L JL   Katsanis Nicholas N   Bostwick Bret B   Popp Bernt B   Davis Erica E EE   Yang Yaping Y  

American journal of human genetics 20170921 4


Bromodomain PHD finger transcription factor (BPTF) is the largest subunit of nucleosome remodeling factor (NURF), a member of the ISWI chromatin-remodeling complex. However, the clinical consequences of disruption of this complex remain largely uncharacterized. BPTF is required for anterior-posterior axis formation of the mouse embryo and was shown to promote posterior neuroectodermal fate by enhancing Smad2-activated wnt8 expression in zebrafish. Here, we report eight loss-of-function and two m  ...[more]

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