BackgroundMoyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown.Methodology/Principal FindingsGenome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10-4). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P = 10−119). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels.Conclusions/SignificanceWe provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease.

The increase in the number of chronic kidney disease (CKD) patients from the north central region of Sri Lanka has become a environmental health issue of national concern. Unlike in other countries where long-standing diabetes and hypertension are the leading causes of renal diseases, the majority of CKD patients from this part of Sri Lanka do not show any identifiable cause. As the disease is restricted to a remarkably specific geographical terrain, particularly in the north central dry zone of the country, multidisciplinary in-depth research studies are required to identify possible etiologies and risk factors. During this study, population screening in the prevalent region and outside the region, analysis of geoenvironmental and biochemical samples were carried out. Population screening that was carried out using a multistage sampling technique indicated that the point prevalence of CKD with uncertain etiology is about 2-3% among those above 18 years of age. Drinking water collected from high-prevalent and non-endemic regions was analyzed for their trace and ultratrace element contents, including the nephrotoxic heavy metals Cd and U using ICP-MS. The results indicate that the affected regions contain moderate to high levels of fluoride. The Cd contents in drinking water, rice from affected regions and urine from symptomatic and non-symptomatic patients were much lower indicating that Cd is not a contributing factor for CKD with uncertain etiology in Sri Lanka. Although no single geochemical parameter could be clearly and directly related to the CKD etiology on the basis of the elements determined during this study, it is very likely that the unique hydrogeochemistry of the drinking water is closely associated with the incidence of the disease.

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Chicken B lymphocyte precursors and DT40 cells diversify their immunoglobulin-variable (IgV) genes through homologous recombination (HR)-mediated Ig gene conversion. To identify DNA polymerases that are involved in Ig gene conversion, we created DT40 clones deficient in DNA polymerase eta (poleta), which, in humans, is defective in the variant form of xeroderma pigmentosum (XP-V). Poleta is an error-prone translesion DNA synthesis polymerase that can bypass UV damage-induced lesions and is involved in IgV hypermutation. Like XP-V cells, poleta-disrupted (poleta) clones exhibited hypersensitivity to UV. Remarkably, poleta cells showed a significant decrease in the frequency of both Ig gene conversion and double-strand break-induced HR when compared to wild-type cells, and these defects were reversed by complementation with human poleta. Our findings identify a DNA polymerase that carries out DNA synthesis for physiological HR and provides evidence that a single DNA polymerase can play multiple cellular roles.

Perfluorooctanoate and Perfluorooctane Sulfonate Concentrations in Surface Water in Japan: Norimitsu Saito, et al. Institute for Environmental Sciences and Public Health of Iwate Prefecture—Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are synthetic surfactants used in Japan. An epidemiological study of workers exposed to PFOA revealed a significant increase in prostate cancer mortality. A cross‐sectional study of PFOA‐exposed workers showed that PFOA perturbs sex hormone homeostasis. We analyzed their concentrations in surface water samples collected from all over Japan by LC/MS with a solid phase extraction method. The lowest limits of detection (LOD) (ng/L) were 0.06 for PFOA and 0.04 for PFOS. The lowest limits of quantification (LOQ) (ng/L) were 0.1 for both analytes. The levels [geometric mean (GM); geometric standard deviation (GS)] (ng/L) of PFOA and PFOS in the surface waters were GM (GS): 0.97 (3.06) and 1.19 (2.44) for Hokkaido‐Tohoku (n=16); 2.84(3.56) and 3.69 (3.93) for Kanto (n=14); 2.50 (2.23) and 1.07 (2.36) for Chubu (n=17); 21.5 (2.28) and 5.73 (3.61) for Kinki (n=8); 1.51 (2.28) and 1.00 (3.42) for Chugoku (n=9); 1.93 (2.40) and 0.89 (3.09) for Kyushu‐Shikoku (n=15). The GM of PFOA in Kinki was significantly higher than in other areas (ANOVA p<0.01). Systematic searches of Yodo and Kanzaki Rivers revealed two highly contaminated sites, a public‐water‐disposal site for PFOA and an airport for PFOS. The former was estimated to release 18 kg of PFOA/d. PFOA in drinking water in Osaka city [40 (1.07) ng/L] was significantly higher than in other areas. The present study confirms that recognizable amounts of PFOA are released in the Osaka area and that people are exposed to PFOA through drinking water ingestion.