Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.     

The long and winding road from correlation to causation

Follow-up studies of a Crohn's disease risk locus encompassing IRGM have revealed unexpected complexity. A new study shows that a synonymous variant in the IRGM coding region alters a binding site for miR-196 and modulates IRGM-dependent autophagy, adding to the list of possible mechanisms by which this locus influences disease risk.     

Role of the ubiquitin–proteasome system in the regulation of P2Y13 receptor expression: impact on hepatic HDL uptake

The protective effect of high density lipoproteins (HDL) against atherosclerosis is mainly attributed to their capacity to transport excess cholesterol from peripheral tissues back to the liver for further elimination into the bile, a process called reverse cholesterol transport (RCT). Recently, the importance of the P2Y₁₃ receptor (P2Y₁₃-R) was highlighted in HDL metabolism since HDL uptake by the liver was decreased in P2Y₁₃-R deficient mice, which translated into impaired RCT. Here, we investigated for the first time the molecular mechanisms regulating cell surface expression of P2Y₁₃-R. When transiently expressed, P2Y₁₃-R was mainly detected in the endoplasmic reticulum (ER) and strongly subjected to proteasome degradation while its homologous P2Y₁₂ receptor (P2Y₁₂-R) was efficiently targeted to the plasma membrane. We observed an inverse correlation between cell surface expression and ubiquitination level of P2Y₁₃-R in the ER, suggesting a close link between ubiquitination of P2Y₁₃-R and its efficient targeting to the plasma membrane. The C-terminus tail exchange between P2Y₁₃-R and P2Y₁₂-R strongly restored plasma membrane expression of P2Y₁₃-R, suggesting the involvement of the intra-cytoplasmic tail of P2Y₁₃-R in expression defect. Accordingly, proteasomal inhibition increased plasma membrane expression of functionally active P2Y₁₃-R in hepatocytes, and consequently stimulated P2Y₁₃-R-mediated HDL endocytosis. Importantly, proteasomal inhibition strongly potentiated HDL hepatic uptake (>200 %) in wild-type but not in P2Y₁₃-R-deficient mice, thus reinforcing the role of P2Y₁₃-R expression in regulating HDL metabolism. Therefore, specific inhibition of the ubiquitin–proteasome system might be a novel powerful HDL therapy to enhance P2Y₁₃-R expression and consequently promote the overall RCT.     

Connexin 43 a check-point component of cell proliferation implicated in a wide range of human testis diseases

Gap junction channels link cytoplasms of adjacent cells. Connexins, their constitutive proteins, are essential in cell homeostasis and are implicated in numerous physiological processes. Spermatogenesis is a sophisticated model of germ cell proliferation, differentiation, survival, and apoptosis, in which a connexin isotype, connexin 43, plays a crucial role as evidenced by genomic approaches based on gene deletion. The balance between cell proliferation/differentiation/apoptosis is a prerequisite for maintaining levels of spermatozoa essential for fertility and for limiting anarchic cell proliferation, a major risk of testis tumor. The present review highlights the emerging role of connexins in testis pathogenesis, focusing specifically on two intimately interconnected human testicular diseases (azoospermia with impaired spermatogenesis and testicular germ cell tumors), whose incidence increased during the last decades. This work proposes connexin 43 as a potential cancer diagnostic and prognostic marker, as well as a promising therapeutic target for testicular diseases.     

Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus

We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection (TAAD) and patent ductus arteriosus (PDA) and mapped the disease locus to 16p12.2-p13.13 (ref. 3). We now demonstrate that the disease is caused by mutations in the MYH11 gene affecting the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, a specific contractile protein of smooth muscle cells (SMC). All individuals bearing the heterozygous mutations, even if asymptomatic, showed marked aortic stiffness. Examination of pathological aortas showed large areas of medial degeneration with very low SMC content. Abnormal immunological recognition of SM-MHC and the colocalization of wild-type and mutant rod proteins in SMC, in conjunction with differences in their coimmunoprecipitation capacities, strongly suggest a dominant-negative effect. Human MYH11 gene mutations provide the first example of a direct change in a specific SMC protein leading to an inherited arterial disease.     

The twins and the bucket: How Einstein made gravity rather than motion relative in general relativity

In publications in 1914 and 1918, Einstein claimed that his new theory of gravity in some sense relativizes the rotation of a body with respect to the distant stars (a stripped-down version of Newton's rotating bucket experiment) and the acceleration of the traveler with respect to the stay-at-home in the twin paradox. What he showed was that phenomena seen as inertial effects in a space-time coordinate system in which the non-accelerating body is at rest can be seen as a combination of inertial and gravitational effects in a (suitably chosen) space-time coordinate system in which the accelerating body is at rest. Two different relativity principles play a role in these accounts: (a) the relativity of non-uniform motion, in the weak sense that the laws of physics are the same in the two space-time coordinate systems involved; (b) what Einstein in 1920 called the relativity of the gravitational field, the notion that there is a unified inertio-gravitational field that splits differently into inertial and gravitational components in different coordinate systems. I provide a detailed reconstruction of Einstein's rather sketchy accounts of the twins and the bucket and examine the role of these two relativity principles. I argue that we can hold on to (b) but that (a) is either false or trivial.     

A mixture likelihood approach for generalized linear models

A mixture model approach is developed that simultaneously estimates the posterior membership probabilities of observations to a number of unobservable groups or latent classes, and the parameters of a generalized linear model which relates the observations, distributed according to some member of the exponential family, to a set of specified covariates within each Class. We demonstrate how this approach handles many of the existing latent class regression procedures as special cases, as well as a host of other parametric specifications in the exponential family heretofore not mentioned in the latent class literature. As such we generalize the McCullagh and Nelder approach to a latent class framework. The parameters are estimated using maximum likelihood, and an EM algorithm for estimation is provided. A Monte Carlo study of the performance of the algorithm for several distributions is provided, and the model is illustrated in two empirical applications.     

A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1

Cell adhesion to extracellular matrix (ECM) proteins is crucial for the structural integrity of tissues and epithelial-mesenchymal interactions mediating organ morphogenesis. Here we describe how the loss of a cytoplasmic multi-PDZ scaffolding protein, glutamate receptor interacting protein 1 (GRIP1), leads to the formation of subepidermal hemorrhagic blisters, renal agenesis, syndactyly or polydactyly and permanent fusion of eyelids (cryptophthalmos). Similar malformations are characteristic of individuals with Fraser syndrome and animal models of this human genetic disorder, such as mice carrying the blebbed mutation (bl) in the gene encoding the Fras1 ECM protein. GRIP1 can physically interact with Fras1 and is required for the localization of Fras1 to the basal side of cells. In one animal model of Fraser syndrome, the eye-blebs (eb) mouse, Grip1 is disrupted by a deletion of two coding exons. Our data indicate that GRIP1 is required for normal cell-matrix interactions during early embryonic development and that inactivation of Grip1 causes Fraser syndrome-like defects in mice.