1. Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features
- Author
-
Alan Fryer, Rolph Pfundt, Lori A. Carpenter, Susan M. White, Kirsten P. Forbes, Daniela T. Pilz, Nava Shaul-Lotan, Andrew E. Fry, Anthonie J. van Essen, Amy E. Roberts, A. Micheil Innes, Katherine A. Fawcett, Beatriz Paumard-Hernández, Michael Wright, Peter D. Turnpenny, Blanca Gener, Richard Caswell, Lindsay B. Henderson, Romana Gjergja-Juraski, Melissa Sloman, Wendy K. Chung, Karen E. Heath, G. Bradley Schaefer, Heather M. McLaughlin, and Erica H. Gerkes
- Subjects
0301 basic medicine ,EXPRESSION ,PCGF2 ,Polycomb Group Ring Finger 2 ,MEL-18 ,Mutant ,dysmorphism ,PROTEIN ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Report ,Histone H2A ,Genetics ,Gene silencing ,Missense mutation ,polymicrogyria ,Craniofacial ,SPECIFICATION ,Gene ,MEL18 ,intellectual disability ,Genetics (clinical) ,CYCLIN D2 ,UBIQUITYLATION ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,REPRESSION ,Correction ,Phenotype ,GENE ,030104 developmental biology ,Histone ,030220 oncology & carcinogenesis ,biology.protein ,HISTONE H2A ,STEM-CELLS - Abstract
PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.
- Published
- 2018