Investigating targettable pathways in Robinow Syndrome

Individuals with Robinow syndrome, a genetic condition, are born with a wider midface, and shorter stature. In addition to the congenital anomalies, a subset of adolescent patients with Robinow syndrome develop bony overgrowths that impinge on the cranial nerve foramina leading to significant co-morbidities including pain. Robinow Syndrome is caused by mutations in core components of the Wnt/Planar cell polarity (Wnt/PCP) signaling pathway. Wnt/PCP signaling regulates neighbor relationships through the protein-protein interactions of its core components including Prickle1 and Dishevelled. We have determined that the Prickle1Bj/Bj mice are an excellent model for Robinow Syndrome. The Prickle1Bj/Bj mice have a wider midface, and shortened limbs. While, thus far, there is no report of Robinow patients with Prickle1 mutations, Prickle1 protein function serves as the common mechanistic link between all of the known patient mutations in Robinow Syndrome. Prickle1Bj/Bj growth plates have randomized chondrocyte polarity as a result of decreased protein-protein interactions between Prickle1Bj and Dvl2 or Dvl3. The consequence of the diminished protein interactions is increased Hedgehog signaling in the Prickle1Bj/Bj cranial base compared to controls. In response to increased HH signaling, the Prickle1Bj/Bj cranial base growth plates undergo precocious maturation which prevents its proximal-distal expansion resulting in the wider midface, and shorter stature. In addition, the Prickle1Bj/Bj primary cilia are shortened and swollen. In this proposal, I will test the hypothesis that Prickle1 is necessary for ciliogenesis, and the swollen cilia in Prickle1Bj/Bj mutants results in increased HH signaling. We will determine if the increased HH signaling is the primary cause of the Prickle1Bj/Bj skeletal anomalies by dampening HH signaling. In addition, we will determine if dampening HH signaling in human patient derived fibroblasts can modify the disease phenotype

Trps1 Regulates Development of Craniofacial Skeleton and Is Required for the Initiation of Palatal Shelves Fusion

Trichorhinophalangeal syndrome (TRPS) is an autosomal dominant disorder resulting from heterozygous mutations of the TRPS1 gene. Common craniofacial abnormalities in TRPS patients include micrognathia, hypoplastic zygomatic arch, high-arched palate, and, occasionally, cleft palate. Studies have demonstrated that mice with a heterozygous Trps1 mutation (Trps1+/− mice) have similar features to patients with TRPS, including high-arched palates. However, mice with a homozygous Trps1 mutation (Trps1−/− mice) exhibit similar but more severe abnormalities, including cleft palate. Our study aimed to characterize the craniofacial phenotype to understand the role of Trps1 in craniofacial development and gain insight on the cleft palate pathogenesis in Trps1 deficiency. Whole-mount skeletal staining revealed hypoplastic skeletal and cartilaginous elements, steep nasal slope, and missing presphenoid in Trps1−/− mice. Although several craniofacial skeleton elements were abnormal in Trps1−/− mice, the Trps1 deficiency did not appear to disrupt cranial vault development. All Trps1−/− mice presented with cleft palate. Analyses of Trps1 expression during palatogenesis detected Trps1 mRNA and protein in palatal mesenchyme and in specific regions of palatal epithelium, which suggested that Trps1 is involved in palatal fusion. Ex vivo culture experiments demonstrated that Trps1−/− palatal shelves were unable to initiate the fusion process. On the molecular level, Trps1 deficiency resulted in decreased epithelial expression of proteins involved in palatal fusion, including chondroitin sulfate proteoglycan, transforming growth factor-beta 3, Twist1, and beta-catenin. Mesenchymal expression of chondroitin sulfate proteoglycan expression was unaffected, indicating a cell type-specific mechanism of Trps1 regulation on chondroitin sulfate proteoglycan. In conclusion, we demonstrated that Trps1 is involved in the development of craniofacial skeletal elements and in the initiation of the palatal shelves fusion. Furthermore, our studies uncovered that Trps1 is required for epithelial expression of several proteins involved in the palatal shelves fusion

Craniofacial dysmorphology in 22q11.2 deletion syndrome by 3D laser surface imaging and geometric morphometrics: illuminating the developmental relationship to risk for psychosis

Persons with 22q11.2 deletion syndrome (22q11.2DS) are characterized inter alia by facial dysmorphology and greatly increased risk for psychotic illness. Recent studies indicate facial dysmorphology in adults with schizophrenia. This study evaluates the extent to which the facial dysmorphology of 22q11.2DS is similar to or different from that evident in schizophrenia. Twenty-one 22q11.2DS-sibling control pairs were assessed using 3D laser surface imaging. Geometric morphometrics was applied to 30 anatomical landmarks, 480 geometrically homologous semi-landmarks on curves and 1720 semi-landmarks interpolated on each 3D facial surface. Principal component (PC) analysis of overall shape space indicated PC2 to strongly distinguish 22q11.2DS from controls. Visualization of PC2 indicated 22q11.2DS and schizophrenia to be similar in terms of overall widening of the upper face, lateral displacement of the eyes/orbits, prominence of the cheeks, narrowing of the lower face, narrowing of nasal prominences and posterior displacement of the chin; they differed in terms of facial length (increased in 22q11.2DS, decreased in schizophrenia), mid-face and nasal prominences (displaced upwards and outwards in 22q11.2DS, less prominent in schizophrenia); lips (more prominent in 22q11.2DS; less prominent in schizophrenia) and mouth (open mouth posture in 22q11.2DS; closed mouth posture in schizophrenia). These findings directly implicate dysmorphogenesis in a cerebral-craniofacial domain that is common to 22q11.2DS and schizophrenia and which may repay further clinical and genetic interrogation in relation to the developmental origins of psychotic illness

Novel links between ciliopathies and FGF-related craniofacial syndromes

K Liu1*, JT Tabler1, HL Szabo-Rogers1, A Mesbahi1, C Healy1, W Barrell1, B Wlodarczyk2, Author Affiliations 1 King's College London, UK 2 University of Texas Southwestern, USA 3 University of Texas at Austin, USAOral Presentation : Recent studies suggest that planar cell polarity (PCP) genes coordinate cell polarity, ciliogenesis and signalling during mammalian development. FUZ is a PCP gene implicated in human congenital anomalies, including neural tube defects and orofacial clefting. Our analysis of fuzzy mutant mice reveals ciliogenesis defects in craniofacial tissues as well as a suite of phenotypes reminiscent of FGF-related craniofacial disorders. Mutants have coronal synostosis, shortened facial extensions, low-set ears and a high-arched palate. To our surprise, we found that the facial defects are due to increased neural crest migration into the first branchial arch (BA1), resulting in maxillary hyperplasia. Furthermore, the neural crest cells migrate in a disorganized fashion, deeper than normal and with fewer cell-cell contacts. This ectopic migration correlates with a dramatic increase in FGF signaling, first in the mid-hindbrain boundary, and then in the BA1 epithelia. The increased tissue causes a medial positional shift in the palatal primordia that manifests as a high-arched palate with pseudo-cleft. Genetic loss of fgf8 rescues the maxillary hyperplasia. Taken together, our data suggest a novel interplay between ciliogenesis, FGF signalling and migration of neural crest which may underlie congenital craniofacial dysmorphologies.Molecular [email protected]

Niche as a determinant of word fate in online groups

Patterns of word use both reflect and influence a myriad of human activities and interactions. Like other entities that are reproduced and evolve, words rise or decline depending upon a complex interplay between {their intrinsic properties and the environments in which they function}. Using Internet discussion communities as model systems, we define the concept of a word niche as the relationship between the word and the characteristic features of the environments in which it is used. We develop a method to quantify two important aspects of the size of the word niche: the range of individuals using the word and the range of topics it is used to discuss. Controlling for word frequency, we show that these aspects of the word niche are strong determinants of changes in word frequency. Previous studies have already indicated that word frequency itself is a correlate of word success at historical time scales. Our analysis of changes in word frequencies over time reveals that the relative sizes of word niches are far more important than word frequencies in the dynamics of the entire vocabulary at shorter time scales, as the language adapts to new concepts and social groupings. We also distinguish endogenous versus exogenous factors as additional contributors to the fates of words, and demonstrate the force of this distinction in the rise of novel words. Our results indicate that short-term nonstationarity in word statistics is strongly driven by individual proclivities, including inclinations to provide novel information and to project a distinctive social identity.Comment: Supporting Information is available here: http://www.plosone.org/article/fetchSingleRepresentation.action?uri=info:doi/10.1371/journal.pone.0019009.s00

CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2–DOP receptor heterodimer

Opioid agonists have a broad range of effects on cells of the immune system, including modulation of the inflammatory response, and opioid and chemokine receptors are co-expressed by many white cells. Hetero-oligomerization of the human DOP opioid and chemokine CXCR2 receptors could be detected following their co-expression by each of co-immunoprecipitation, three different resonance energy transfer techniques and the construction of pairs of individually inactive but potentially complementary receptor G-protein α subunit fusion proteins. Although DOP receptor agonists and a CXCR2 antagonist had no inherent affinity for the alternative receptor when either receptor was expressed individually, use of cells that expressed a DOP opioid receptor construct constitutively, and in which expression of a CXCR2 receptor construct could be regulated, demonstrated that the CXCR2 antagonist enhanced the function of DOP receptor agonists only in the presence of CXCR2. This effect was observed for both enkephalin- and alkaloid-based opioid agonists, and the effective concentrations of the CXCR2 antagonist reflected CXCR2 receptor occupancy. Entirely equivalent results were obtained in cells in which the native DOP opioid receptor was expressed constitutively and in which expression of the isolated CXCR2 receptor could be induced. These results indicate that a CXCR2 receptor antagonist can enhance the function of agonists at a receptor for which it has no inherent direct affinity by acting as an allosteric regulator of a receptor that is a heterodimer partner for the CXCR2 receptor. These results have novel and important implications for the development and use of small-molecule therapeutics

The Cyprinodon variegatus genome reveals gene expression changes underlying differences in skull morphology among closely related species

Genes in durophage intersection set at 15 dpf. This is a comma separated table of the genes in the 15 dpf durophage intersection set. Given are edgeR results for each pairwise comparison. Columns indicating whether a gene is included in the intersection set at a threshold of 1.5 or 2 fold are provided. (CSV 13 kb

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD

Cost-Effectiveness of Male Circumcision for HIV Prevention in a South African Setting

BACKGROUND: Consistent with observational studies, a randomized controlled intervention trial of adult male circumcision (MC) conducted in the general population in Orange Farm (OF) (Gauteng Province, South Africa) demonstrated a protective effect against HIV acquisition of 60%. The objective of this study is to present the first cost-effectiveness analysis of the use of MC as an intervention to reduce the spread of HIV in sub-Saharan Africa. METHODS AND FINDINGS: Cost-effectiveness was modeled for 1,000 MCs done within a general adult male population. Intervention costs included performing MC and treatment of adverse events. HIV prevalence was estimated from published estimates and incidence among susceptible subjects calculated assuming a steady-state epidemic. Effectiveness was defined as the number of HIV infections averted (HIA), which was estimated by dynamically projecting over 20 years the reduction in HIV incidence observed in the OF trial, including secondary transmission to women. Net savings were calculated with adjustment for the averted lifetime duration cost of HIV treatment. Sensitivity analyses examined the effects of input uncertainty and program coverage. All results were discounted to the present at 3% per year. For Gauteng Province, assuming full coverage of the MC intervention, with a 2005 adult male prevalence of 25.6%, 1,000 circumcisions would avert an estimated 308 (80% CI 189–428) infections over 20 years. The cost is $181 (80$117–$306) per HIA, and net savings are$2.4 million (80% CI $1.3 million to$3.6 million). Cost-effectiveness is sensitive to the costs of MC and of averted HIV treatment, the protective effect of MC, and HIV prevalence. With an HIV prevalence of 8.4%, the cost per HIA is $551 (80$344–$1,071) and net savings are$753,000 (80% CI $0.3 million to$1.2 million). Cost-effectiveness improves by less than 10% when MC intervention coverage is 50% of full coverage. CONCLUSIONS: In settings in sub-Saharan Africa with high or moderate HIV prevalence among the general population, adult MC is likely to be a cost-effective HIV prevention strategy, even when it has a low coverage. MC generates large net savings after adjustment for averted HIV medical costs