Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency
| Autor: | David J. Amor, Elizabeth Fitzpatrick, Paul J. Lockhart, Kate Pope, Richard J. Leventer, Susan M. White, Anneke T. Vulto-van Silfhout, Hayley S. Mountford, Pernille Mathiesen Tørring, Shane McKee, Donna M. Muzny, Joe C H Sim, Greta Gillies, Martin B. Delatycki, Shalini N. Jhangiani, Gabrielle R. Wilson |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Nonsense mutation Micrognathism Intellectual disability Chromatin remodelling Haploinsufficiency Biology Cell cycle Frameshift mutation medicine Humans Genetics(clinical) Pharmacology (medical) Abnormalities Multiple Coffin-Siris syndrome ARID1B mutation Coffin–Siris syndrome GeneralLiterature_REFERENCE(e.g. dictionaries encyclopedias glossaries) Genetics (clinical) 2. Zero hunger Genetics Medicine(all) Research Cell Cycle General Medicine medicine.disease Chromatin Assembly and Disassembly Phenotype Human genetics DNA-Binding Proteins Face Female Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7] Hand Deformities Congenital Neck Transcription Factors |
| Zdroj: | Orphanet Journal of Rare Diseases, 9, 1, pp. 43 Orphanet Journal of Rare Diseases, 9, 43 Orphanet Journal of Rare Diseases Sim, J C H, White, S M, Fitzpatrick, E, Wilson, G R, Gillies, G, Pope, K, Mountford, H S, Tørring, P M, McKee, S, Vulto-van Silfhout, A T, Jhangiani, S N, Muzny, D M, Leventer, R J, Delatycki, M B, Amor, D J & Lockhart, P J 2014, ' Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency ', Orphanet Journal of Rare Diseases, vol. 9, 43 . https://doi.org/10.1186/1750-1172-9-43 |
| ISSN: | 1750-1172 |
| Popis: | Background: Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. Here, we investigate the molecular basis of a patient with an overlapping but distinctive phenotype of intellectual disability, plantar fat pads and facial dysmorphism. Methods/results: High density microarray analysis of the patient demonstrated a heterozygous deletion at 6q25.3, which resulted in the loss of four genes including AT Rich Interactive Domain 1B (ARID1B). Subsequent quantitative real-time PCR analysis revealed ARID1B haploinsufficiency in the patient. Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S-1 phase. Based on the patient's distinctive phenotype, we ascertained four additional patients and identified heterozygous de novo ARID1B frameshift or nonsense mutations in all of them. Conclusions: This study broadens the spectrum of ARID1B associated phenotypes by describing a distinctive phenotype including plantar fat pads but lacking the hypertrichosis or fifth nail hypoplasia associated with Coffin-Siris syndrome. We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency. |
| Databáze: | OpenAIRE |
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