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Han-Xiang Deng, Teepu Siddique and colleagues report that scapuloperoneal spinal muscular atrophy and hereditary motor and sensory neuropathy type IIC are allelic disorders caused by mutations in TRPV4. Their functional studies indicate that the mutations result in increased calcium channel activity.
Michaela Auer-Grumbach and colleagues report that missense alterations in the N-terminal ankyrin domain of TRPV4 underlie three distinct autosomal dominant disorders of the peripheral nervous system. Alterations in other regions of TRPV4 have been shown to underlie a family of autosomal dominant skeletal dysplasias, underscoring the marked clinical heterogeneity associated with mutations in this channel.
Charlotte Sumner and colleagues report that mutations in the ankyrin repeat region of TRPV4 cause Charcot-Marie-Tooth disease type 2C. Their functional studies indicate that the mutations result in increased channel activity.
Martin Pollak and colleagues show that missense mutations in the diaphanous inhibitory domain of INF2 cause focal segmental glomerular sclerosis. INF2 encodes a member of the formin family of actin-regulating proteins, highlighting an important role for actin dynamics in podocyte function.
Nicholas Hastie and colleagues show that Wt1 is required for the epithelial-to-mesenchymal (EMT) transition in the developing epicardium and the formation of mesenchymal cardiovascular progenitors. Wt1 directly regulates the transcription of Snail and E-cadherin, two well-known mediators of EMT.
Liang Zhu and colleagues report that inactivation of Skp2, a target of the pRb tumor suppressor, completely prevented tumorigenesis in tumor-prone mice with loss of one Rb1 allele. This work nominates Skp2 as a drug target to combat Rb1-deficient tumors.
Chris Wallace and colleagues report the identification of a new locus on chromosome 14q32.3 that alters susceptibility to type 1 diabetes with a parent-of-origin effect. The region contains imprinted genes including DLK1 and MEG3.
Germline mutations in PARK2 are a well-known cause of the neurodegenerative disorder Parkinson's disease. Here, Timothy Chan and colleagues report somatic mutations and intragenic deletions of PARK2 in glioblastoma, colon cancer and lung cancer.
Steven McCarroll and colleagues examine common gene deletions in individuals that have undergone bone marrow transplantation. They find that risk of acute graft-versus-host disease is greater when the donor and recipient are mismatched for a homozygous deletion of UGT2B17.
Hakon Hakonarson and colleagues report the discovery of five new regions associated with susceptibility to early-onset inflammatory bowel disease. They also identify multiple loci previously implicated in the etiology of adult-onset Crohn's disease and/or ulcerative colitis as risk factors for early-onset forms of these diseases.
Michiaki Kubo and colleagues report results of a genome-wide association study of ulcerative colitis in the Japanese population. Their study identifies three new susceptibility loci for this common inflammatory bowel disease, including FCGR2A, which has previously been implicated in other autoimmune diseases.
The UK IBD Genetics Consortium and the Wellcome Trust Case Control Consortium 2 report results of a genome-wide association study of ulcerative colitis. They identify three new loci associated with the disease, including the HNF4A region on 20q13.
Tatsushi Toda and colleagues report results of a genome-wide association study of Parkinson's disease in the Japanese population. They identify four loci harboring common variants associated with Parkinson's disease, including two newly discovered risk regions on 1q32 and 4p15.
Andrew Singleton, Thomas Gasser and colleagues report results of a genome-wide association study of Parkinson's disease among individuals of European ancestry. They find genome-wide significant associations at two loci, SNCA and MAPT, and provide supporting evidence for a new risk locus on 1q32.
Karin Lundberg and colleagues explore gene-gene and gene-environment interactions in susceptibility to rheumatoid arthritis, reporting an association of HLA-DRB1, PTPN22 and smoking stratified by the autoantigen CEP-1.
Soumya Raychaudhuri and colleagues demonstrate the utility of GRAIL, a software program used to prioritize results from genome-wide association studies for further replication, applied here to rheumatoid arthritis. The authors seek replication of their predictions in additional independent cohorts and report three new genetic loci associated with RA susceptibility.
Andrew Feinberg and colleagues show that differential methylation of CpG island shores distinguish human induced pluripotent stem cells from the fibroblasts from which they were derived. These differentially methylated regions of the genome can also distinguish normal colon tissue from colorectal cancer.
Andrew Wilkie and colleagues report that activating paternal-effect mutations in FGFR3 and HRAS promote clonal expansion in the testis, leading to spermatocytic seminomas. The same mutation in FGFR3 leads to the lethal disorder thanatophoric dysplasia, revealing a shared genetic mechanism for congenital disorders and testicular tumors.