Purpose Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical... Show morePurpose Sifrim-Hitz-Weiss syndrome (SIHIWES) is a recently described multisystemic neurodevelopmental disorder caused by de novo variants inCHD4. In this study, we investigated the clinical spectrum of the disorder, genotype-phenotype correlations, and the effect of different missense variants on CHD4 function. Methods We collected clinical and molecular data from 32 individuals with mostly de novo variants in CHD4, identified through next-generation sequencing. We performed adenosine triphosphate (ATP) hydrolysis and nucleosome remodeling assays on variants from five different CHD4 domains. Results The majority of participants had global developmental delay, mild to moderate intellectual disability, brain anomalies, congenital heart defects, and dysmorphic features. Macrocephaly was a frequent but not universal finding. Additional common abnormalities included hypogonadism in males, skeletal and limb anomalies, hearing impairment, and ophthalmic abnormalities. The majority of variants were nontruncating and affected the SNF2-like region of the protein. We did not identify genotype-phenotype correlations based on the type or location of variants. Alterations in ATP hydrolysis and chromatin remodeling activities were observed in variants from different domains. Conclusion The CHD4-related syndrome is a multisystemic neurodevelopmental disorder. Missense substitutions in different protein domains alter CHD4 function in a variant-specific manner, but result in a similar phenotype in humans. Show less
Eijk, E. van; Paschalis, V.; Green, M.; Friggen, A.H.; Larson, M.A.; Spriggs, K.; ... ; Smits, W.K. 2016
In this thesis, the characteristics of the Escherichia coli UvrA protein were analyzed with microscopy techniques that allow detection of protein complexes at the single-molecule level. Together... Show moreIn this thesis, the characteristics of the Escherichia coli UvrA protein were analyzed with microscopy techniques that allow detection of protein complexes at the single-molecule level. Together with UvrB and UvrC, UvrA catalyzes the excision of damaged DNA from the bacterial genome. This DNA repair mechanism is called Nucleotide Excision Repair (NER) and is also conserved in higher organisms. In the current model for bacterial NER, DNA repair is initiated by a complex of two UvrA and two UvrB subunits, the A2B2-complex. In this complex, the two UvrA subunits probe the genome for potential lesions. The mechanism of DNA damage recognition by UvrA is further revealed in this thesis. Show less
