A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant 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 strategie

Proton/Hydrogen Transfer Affects the S-State-Dependent Microsecond Phases of P680+ Reduction during Water Splitting

Original article can be found at: http://pubs.acs.org/journals/bichaw/index.html Copyright American Chemical Society DOI: 10.1021/bi9713815 [Full text of this article is not available in the UHRA]To investigate a possible coupling between P680+ reduction and hydrogen transfer, we studied the effects of H2O/D2O exchange on the P680+ reduction kinetics in the nano- and microsecond domains. We concentrated on studying the period-4 oscillatory (i.e., S-state-related) part of the reduction kinetics, by analyzing the differences between the P680+ reduction curves, rather than the full kinetics. Earlier observations that P680+ reduction kinetics have microsecond components were confirmed: the longest observable lifetime whose amplitude showed period-4 oscillations was 30 μs. We found that solvent isotope exchange left the nanosecond phases of the P680+ reduction unaltered. However, a significant effect on the oscillatory microsecond components was observed. We propose that, at least in the S0/S1 and S3/S0 transitions, hydrogen (proton) transfer provides an additional decrease in the free energy of the YZ+P680 state with respect to the YZP680+ state. This implies that relaxation of the state YZ+P680 is required for complete reduction of P680+ and for efficient water splitting. The kinetics of the P680+ reduction suggest that it is intraprotein proton/hydrogen rearrangement/transfer, rather than proton release to the bulk, which is occurring on the 1−30 μs time scale.Peer reviewe

A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. De novo dominant 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