Cargando…

Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency

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 predominan...

Descripción completa

Detalles Bibliográficos
Autores principales: Sim, Joe C H, White, Susan M, Fitzpatrick, Elizabeth, Wilson, Gabrielle R, Gillies, Greta, Pope, Kate, Mountford, Hayley S, Torring, Pernille M, McKee, Shane, Vulto-van Silfhout, Anneke T, Jhangiani, Shalini N, Muzny, Donna M, Leventer, Richard J, Delatycki, Martin B, Amor, David J, Lockhart, Paul J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022252/
https://www.ncbi.nlm.nih.gov/pubmed/24674232
http://dx.doi.org/10.1186/1750-1172-9-43
_version_ 1782316370222907392
author Sim, Joe C H
White, Susan M
Fitzpatrick, Elizabeth
Wilson, Gabrielle R
Gillies, Greta
Pope, Kate
Mountford, Hayley S
Torring, Pernille M
McKee, Shane
Vulto-van Silfhout, Anneke T
Jhangiani, Shalini N
Muzny, Donna M
Leventer, Richard J
Delatycki, Martin B
Amor, David J
Lockhart, Paul J
author_facet Sim, Joe C H
White, Susan M
Fitzpatrick, Elizabeth
Wilson, Gabrielle R
Gillies, Greta
Pope, Kate
Mountford, Hayley S
Torring, Pernille M
McKee, Shane
Vulto-van Silfhout, Anneke T
Jhangiani, Shalini N
Muzny, Donna M
Leventer, Richard J
Delatycki, Martin B
Amor, David J
Lockhart, Paul J
author_sort Sim, Joe C H
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4022252
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-40222522014-05-16 Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency Sim, Joe C H White, Susan M Fitzpatrick, Elizabeth Wilson, Gabrielle R Gillies, Greta Pope, Kate Mountford, Hayley S Torring, Pernille M McKee, Shane Vulto-van Silfhout, Anneke T Jhangiani, Shalini N Muzny, Donna M Leventer, Richard J Delatycki, Martin B Amor, David J Lockhart, Paul J Orphanet J Rare Dis Research 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. BioMed Central 2014-03-27 /pmc/articles/PMC4022252/ /pubmed/24674232 http://dx.doi.org/10.1186/1750-1172-9-43 Text en Copyright © 2014 Sim et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Sim, Joe C H
White, Susan M
Fitzpatrick, Elizabeth
Wilson, Gabrielle R
Gillies, Greta
Pope, Kate
Mountford, Hayley S
Torring, Pernille M
McKee, Shane
Vulto-van Silfhout, Anneke T
Jhangiani, Shalini N
Muzny, Donna M
Leventer, Richard J
Delatycki, Martin B
Amor, David J
Lockhart, Paul J
Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency
title Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency
title_full Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency
title_fullStr Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency
title_full_unstemmed Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency
title_short Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency
title_sort expanding the phenotypic spectrum of arid1b-mediated disorders and identification of altered cell-cycle dynamics due to arid1b haploinsufficiency
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022252/
https://www.ncbi.nlm.nih.gov/pubmed/24674232
http://dx.doi.org/10.1186/1750-1172-9-43
work_keys_str_mv AT simjoech expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT whitesusanm expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT fitzpatrickelizabeth expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT wilsongabrieller expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT gilliesgreta expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT popekate expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT mountfordhayleys expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT torringpernillem expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT mckeeshane expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT vultovansilfhoutanneket expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT jhangianishalinin expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT muznydonnam expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT leventerrichardj expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT delatyckimartinb expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT amordavidj expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency
AT lockhartpaulj expandingthephenotypicspectrumofarid1bmediateddisordersandidentificationofalteredcellcycledynamicsduetoarid1bhaploinsufficiency