A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling
Makaleler > Tam Makale · 2013
Yazarlar: Dagmar WIECZOREK, Nina BOEGERSHAUSEN, Filippo BELEGGIA, Sabine STEINER-HALDENSTAETT, Esther POHL, Yun LI, Esther MILZ, Marcel MARTIN, Holger THIELE, Janine ALTMUELLER, Yasemin Alanay, Hulya Kayserili, Ludger KLEIN-HITPASS, Stefan BOHRINGER, Andreas WOLLSTEIN, Beate ALBRECHT, Koray Boduroglu, Almuth CALIEBE, Krystyna CHRZANOWSKA, Muhsin Özgür ÇOĞULU, Francesca CRISTOFOLI, Johanna Christina CZESCHIK, Koenraad DEVRIENDT, Maria Teresa DOTTI, Nursel Elcioglu, Blanca GENER, Timm O. GOECKE, Malgorzata KRAJEWSKA-WALASEK, Encarnacion GUILLEN-NAVARRO, Joussef HAYEK, Gunnar HOUGE, Esra Kilic, Pelin Ozlem Simsek-Kiper, Vanesa LOPEZ-GONZALEZ, Alma KUECHLER, Stanislas LYONNET, Francesca MARI, Annabella MAROZZA, Michele Mathieu DRAMARD, Barbara MIKAT, Gilles MORIN, Fanny MORICE-PICARD, Feriştah Ferda ÖZKINAY, Anita Rauch, Alessandra RENIERI, Sigrid TINSCHERT, G. Eda Utine, Catheline Vilain, Rossella VIVARELLI, Christiane ZWEIER, Peter NUERNBERG, Sven RAHMANN, Joris VERMEESCH, Hermann-Josef LUEDECKE, Michael ZESCHNIGK, Bernd WOLLNIK
HUMAN MOLECULAR GENETICS, SCI Expanded İndekslerine Giren Dergi, Uluslararası, 2013, cilt 22, ss 5121-5135
DOI: 10.1093/hmg/ddt366
Özet
Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.