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Editors' Picks

        Dedicated to itch

        Pain and itch are both initiated and mediated by primary sensory neurons; however, scientists have long wondered whether the distinct sensations of pain and itch are elicited by different yet specific neurons. In a recent landmark study, Han and colleagues demonstrated that neurons expressing the G protein–coupled receptor MrgprA3, which functions as a receptor for the pruritogen chloroquine, comprise a specific population of itch-mediating neurons in mice. These neurons exclusively innervate the skin, supporting the fact that itch arises only from skin and not from internal tissues such as visceral organs. In addition, these MrgprA3+ neurons responded to multiple chemical pruritogens. Ablation of such cells reduced itch behavior in response to these chemicals, and, importantly, spontaneous scratching from dry skin or from allergic reactions was dramatically decreased, highlighting the possibility of targeting these neurons specifically to relieve itch in human patients. (Nat Neurosci 16:174–82, 2013) Selected by E. Lerner

        License to ill

        The blood–brain barrier protects central nervous system (CNS) tissues from peripheral immune cell attack, although myelin-specific T-cell blasts are thought to enter the CNS and create a proinflammatory environment to facilitate a second autoimmune attack from the leptomeningeal vessels. Recently, in a Lewis rat model of experimental autoimmune encephalomyelitis, Odoardi and colleagues observed that the majority of intravenously transferred T-cell blasts homed to the peripheral lung tissues and then to the bronchus-associated lymphoid tissues and draining lymph nodes before reentering the bloodstream and ultimately reaching the CNS. During this migration, the T cells experience a reprogramming of their gene expression profile to upregulate membrane receptors, chemokine receptors, and adhesion molecules and downregulate proliferation and activation programs. These changes effectively prime the cells to migrate toward inflamed tissues, transgress endothelial barriers, and encounter antigen for activation. Thus, the lung serves as a niche for T-cell reactivation and essentially licensure of the cells to enter the CNS and cause paralytic disease. (Nature 488:675–9, 2012) Selected by M. Amagai

        Hair and nails

        Five clinical forms of pure hair and nail ectodermal dysplasia (PHNED) have been described with either autosomal-recessive or autosomal-dominant inheritance, although the molecular underpinnings of these disorders are just beginning to be explored. Following identification of mutations in KRT85 in a consanguineous Pakistani family affected by PHNED, subsequent studies revealed genetic heterogeneity for autosomal-recessive PHNED. Recently, Lin and colleagues reported homozygous loss-of-function mutations in the homeobox transcription factor gene HOXC13 in affected individuals from a consanguineous Chinese Hui family and a consanguineous Afghan family. Functional analysis revealed that the identified nonsense HOXC13 mutation resulted in little or no expression in the scalp skin tissue. In addition, expression of HOXC13 target genes that are required for hair differentiation and nail development was dramatically decreased in the skin of affected individuals. These results indicate that loss-of-function mutations in HOXC13 underlie PHNED pathology. (Am J Hum Genet 91:906–11, 2012) Selected by J. Uitto

        Unlikely relatives

        The success of genome-wide association studies has led to the discovery of genetic connections between some clinically unrelated diseases. For example, of eight leprosy-susceptibility loci, five have also been reported to be associated with Crohn's disease (CD) and ulcerative colitis. Although leprosy is caused by infection with Mycobacterium leprae, both CD and leprosy are inflammatory diseases, and findings suggest that development of CD may be triggered by mycobacterial infection, supporting the biological relevance of the genetic relationship. Liu and colleagues recently conducted a multiple-stage genetic association study of inflammatory bowel disease (IBD)-susceptibility loci in leprosy samples from a Chinese population and identified two additional shared susceptibility loci. Thus, these findings implicate IL18RAP/IL18R1 and IL12B in leprosy and highlight an important role of IL12/IL18-mediated transcriptional regulation of IFN-γ production in leprosy. Importantly, these results further document shared genetic susceptibility between inflammatory and infectious diseases. (Am J Hum Genet 91:935–41, 2012) Selected by J. Uitto

        Mitochondria function in development

        Mitochondrial disorders are clinically heterogeneous but are typically associated with abnormalities in oxidative phosphorylation and postnatal organ failure. Microphthalmia with linear skin lesions (MLS) is an X-linked male-lethal neurodevelopmental disorder known to result from mutations in holocytochrome c-type synthase (HCCS), a gene involved in the mitochondrial respiratory chain (MRC). Owing to the features of MLS that differ from those of the canonical mitochondrial diseases and the lack of HCCS mutations in several clinically diagnosed MLS cases, Indrieri and colleagues examined the only X-linked member of the CIII–CIV MRC complex—cytochrome c oxidase 7B (COX7B)—and identified mutations in three cases of MLS. In cell culture studies, the COX7B subunit was found to be necessary for COX activity, COX assembly, and mitochondrial respiration. Downregulation of the COX7B ortholog in medaka revealed an essential role for this subunit in development in vertebrates. Thus, these studies demonstrate a role for MRC function in neurodevelopment and indicate that mutation of the CIII–CIV MRC complex underlies specific developmental defects. (Am J Hum Genet 91:942–9, 2012) Selected by J. Uitto