Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylati

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Genetics of disease, diagnosis and treatmen

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive web-based survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features

Landscape-scale variability in soil organic carbon storage in the central Canadian Arctic

Arctic soils constitute a vast, but poorly quantified, pool of soil organic carbon (SOC). The uncertainty associated with pan-Arctic SOC storage estimates - a result of limited SOC and land cover data - needs to be reduced if we are to better predict the impact of future changes to Arctic carbon stocks resulting from climate warming. In this study landscape-scale variability in SOC at a Southern Arctic Ecozone site in the central Canadian Arctic was investigated with the ultimate goal of up-scaling SOC estimates with a land cover classification system. Total SOC was estimated to depths of 30 cm and 50 cm for 76 soil pits, together representing eight different vegetation communities in seven different broad landscape units. Soil organic carbon to 50 cm was lowest for the xerophytic herb community in the esker complex landscape unit (7.2±2.2 SD kg m-2) and highest in the birch hummock terrain in the lowland tundra landscape unit (36.4±2.8 kg m-2), followed by wet sedge and dry sedge communities in the wetland complex (29.8±9.9 and 22.0±2.0 kg m-2, respectively). The up-scaled estimates of mean SOC for the study area (excluding water) were 15.8 kg m-2 (to 50 cm) and 11.6 kg m-2 (to 30 cm). On a landscape scale, soil moisture content was found to have an important influence on SOC variability. Overall, this study highlights the importance of SOC variability at fine scales and its impact on up-scaling SOC in Arctic landscapes

MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.

Ribosomopathies are congenital disorders caused by mutations in the genes encoding ribosomal and other functionally related proteins. They are characterized by anemia, other hematopoietic and developmental abnormalities, and p53 activation. Ribosome assembly requires coordinated expression of many ribosomal protein (RP) genes; however, the regulation of RP gene expression, especially in hematopoietic stem cells (HSCs), remains poorly understood. MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that HSC dysfunction in Mysm1 deficiency is driven by p53; however, the mechanisms of p53 activation remained unclear. Here, we describe the transcriptome of Mysm1-deficient mouse HSCs and identify MYSM1 genome-wide DNA binding sites. We establish a direct role for MYSM1 in RP gene expression and show a reduction in protein synthesis in Mysm1(-/-) HSCs. Loss of p53 in mice fully rescues Mysm1(-/-) anemia phenotype but not RP gene expression, indicating that RP gene dysregulation is a direct outcome of Mysm1 deficiency and an upstream mediator of Mysm1-/phenotypes through p53 activation. We characterize a patient with a homozygous nonsense MYSM1 gene variant, and we demonstrate reduced protein synthesis and increased p53 levels in patient hematopoietic cells. Our work provides insights into the specialized mechanisms regulating RP gene expression in HSCs and establishes a common etiology of MYSM1 deficiency and ribosomopathy syndromes

Wood and Natural Fiber-Based Composites (NFCs)

Yunis-Varon syndrome (YVS) is an autosomal-recessive disorder with cleidocranial dysplasia, digital anomalies, and severe neurological involvement. Enlarged vacuoles are found in neurons, muscle, and cartilage. By whole-exome sequencing, we identified frameshift and missense mutations of FIG4 in affected individuals from three unrelated families. FIG4 encodes a phosphoinositide phosphatase required for regulation of PI(3,5)P2 levels, and thus endosomal trafficking and autophagy. In a functional assay, both missense substitutions failed to correct the vacuolar phenotype of Fig4-null mouse fibroblasts. Homozygous Fig4-null mice exhibit features of YVS, including neurodegeneration and enlarged vacuoles in neurons. We demonstrate that Fig4-null mice also have small skeletons with reduced trabecular bone volume and cortical thickness and that cultured osteoblasts accumulate large vacuoles. Our findings demonstrate that homozygosity or compound heterozygosity for null mutations of FIG4 is responsible for YVS, the most severe known human phenotype caused by defective phosphoinositide metabolism. In contrast, in Charcot-Marie-Tooth disease type 4J (also caused by FIG4 mutations), one of the FIG4 alleles is hypomorphic and disease is limited to the peripheral nervous system. This genotype-phenotype correlation demonstrates that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies. Our results describe a role for PI(3,5)P2 signaling in skeletal development and maintenance. " 2013 The American Society of Human Genetics.",,,,,,"10.1016/j.ajhg.2013.03.020",,,"http://hdl.handle.net/20.500.12104/45773","http://www.scopus.com/inward/record.url?eid=2-s2.0-84877577668&partnerID=40&md5=a873f91c3be593ccfbb3f4aae06f62ec",,,,,,"5",,"American Journal of Human Genetics",,"78