Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.     

Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth

17q11 microdeletions that encompass NF1 cause 5%-10% of cases of neurofibromatosis type 1, and individuals with microdeletions are typically taller than individuals with intragenic NF1 mutations, suggesting that deletion of a neighboring gene might promote human growth. We identified mutations in RNF135, which is within the NF1 microdeletion region, in six families characterized by overgrowth, learning disability, dysmorphic features and variable additional features. These data identify RNF135 as causative of a new overgrowth syndrome and demonstrate that RNF135 haploinsufficiency contributes to the phenotype of NF1 microdeletion cases.     

Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ～110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.     

Gut insulin from Foxo1 loss

Neuroendocrine cells, including those in the gut, have a vast array of functions. A new study shows that conditional inactivation of the gene encoding Foxo1 in mouse intestinal endocrine cells converts them into cells synthesizing and secreting insulin. Ectopic gut insulin production was sufficient to ameliorate glucose control in mice with conditional pancreatic β-cell loss and diabetes mellitus.     

Late Quaternary vegetation and climate in the Escalante River Basin on the central Colorado Plateau

Five alcoves (rock shelters) in the Forty-Mile Canyon—Willow Gulch area of the Escalante River Basin in southeastern Utah yielded rich deposits of late Quaternary macrobotanical remains. The deposits were sampled and the contents identified in order to construct a chronology of vegetational change. Fourteen radiocarbon dates indicate that the fossils were deposited between 12,690 and 7510 yr B.P. (years before present). Ninety-one plant taxa were identified, 62 to species. Six species were common to all alcoves: Gambel oak ( Quercus gambelii ), box-elder ( Acer negundo ), prickly pear ( Opuntia subgenus Platyopuntia), skunkbush ( Rhus aromatica var. trilobata ), serviceberry ( Amelanchier utahensis ), and Indian ricegrass ( Oryzopsis hymenoides ). Late Pleistocene samples (>11,000 yr B.P.) contain extralocal, elevationally depressed species such as Douglas fir ( Pseudotsuga menziesii ), spruce ( Picea sp.), and mountain mahogany ( Cercocarpus ledifolius ), and mesophytic species such as rose ( Rosa woodsii ) and water birch ( Betula occidentalis ). Early Holocene samples (11,000-8000 yr B.P.) contain no elevationally depressed conifers, and the remaining mesophytic species decrease in relative abundance. Reticulated hackberry ( Celtis reticulata ) becomes common. The terminal Early Holocene sample (8000-7000 yr B.P.) contains abundant Gambel oak and prickly pear, but little else. Paleoclimatic interpretations for the Late Pleistocene correspond well to those of most other workers on the Colorado Plateau. Climates that were wetter and at least seasonally cooler than they are today are inferred from the macrobotanical assemblage. However, the increased moisture is attributed to higher stream base levels and increased groundwater rather than directly to increased precipitation. Early Holocene climates are interpreted as warmer and drier than those of the Late Pleistocene but still wetter than the present climate. Groundwater levels appear to be decreasing due to stream entrenchment. Terminal Early Holocene climates were much warmer and at least seasonally drier. By the end of the period, groundwater levels had decreased so much that the alcoves were unable to sustain plant communities; stream base level was probably near the present level.     

Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.     

Cancer spheres from gastric cancer patients provide an ideal model system for cancer stem cell research

Cancer stem cells have been hypothesized to drive the growth and metastasis of tumors. Because they need to be targeted for cancer treatment, they have been isolated from many solid cancers. However, cancer stem cells from primary human gastric cancer tissues have not been isolated as yet. For the isolation, we used two cell surface markers: the epithelial cell adhesion molecule (EpCAM) and CD44. When analyzed by flow cytometry, the EpCAM⁺/CD44⁺ population accounts for 4.5% of tumor cells. EpCAM⁺/CD44⁺ gastric cancer cells formed tumors in immunocompromised mice; however, EpCAM^?/CD44^?, EpCAM⁺/CD44^? and EpCAM^?/CD44⁺ cells failed to do so. Xenografts of EpCAM⁺/CD44⁺ gastric cancer cells maintained a differentiated phenotype and reproduced the morphological and phenotypical heterogeneity of the original gastric tumor tissues. The tumorigenic subpopulation was serially passaged for several generations without significant phenotypic alterations. Moreover, EpCAM⁺/CD44⁺, but not EpCAM^?/CD44^?, EpCAM⁺/CD44^? or EpCAM^?/CD44⁺ cells grew exponentially in vitro as cancer spheres in serum-free medium, maintaining the tumorigenicity. Interestingly, a single cancer stem cell generated a cancer sphere that contained various differentiated cells, supporting multi-potency and self-renewal of a cancer stem cell. EpCAM⁺/CD44⁺ cells had greater resistance to anti-cancer drugs than other subpopulation cells. The above in vivo and in vitro results suggest that cancer stem cells, which are enriched in the EpCAM⁺/CD44⁺ subpopulation of gastric cancer cells, provide an ideal model system for cancer stem cell research.     

Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.     

Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12

We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 x 10(-9) for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.