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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.
Peter Fraser and colleagues report a genome-wide analysis of transcription interactions involving the globin genes in mouse erythroid cells. They demonstrate that the transcription factor Klf1 mediates preferential co-associations between genes it regulates.
Martin Zenker, Marco Tartaglia, Reza Ahmadian and colleagues report the identification of a restricted spectrum of NRAS mutations in individuals with Noonan syndrome. Functional testing revealed that the mutations confer enhanced stimulus-dependent MAPK activation.
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.
Greg Gibson and colleagues report an analysis of gene expression variation in relation to environmental geography and ethnicity in blood leukocyte samples from individuals in rural and urban southern Morocco. The study determined the contributions of geography and ethnicity to associations between genotypes and transcript abundance.
David Hinds and colleagues report that a non-synonymous variant in PNPLA3 is associated with alcoholic liver disease and liver cirrhosis. This result follows previously reported associations of this variant with nonalcoholic fatty liver disease.
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.
Raoul Hennekam and colleagues report the identification of mutations in CCBE1 that cause Hennekam syndrome in humans. Features of Hennekam syndrome include lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics. CCBE1 encodes Collagen and Calcium-Binding EGF domain-1, a secreted protein that has been shown to be required for embryonic lymphangiogenesis in zebrafish.
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.
Mary Carrington and colleagues follow up on an earlier association of a variant upstream of HLA-C to HIV viral load setpoint, showing that this variant is associated with high HLA-C cell surface expression and demonstrating a protective effect of the variant in viral load and disease progression.
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.