DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes

BackgroundCilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.MethodsAmong individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model.ResultsPatients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.ConclusionThese findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.</jats:sec

Association of nutritional status and serum albumin levels with development of toxicity in patients with advanced non-small cell lung cancer treated with paclitaxel-cisplatin chemotherapy: a prospective study

<p>Abstract</p> <p>Background</p> <p>A frequent manifestation of advanced NSCLC is malnutrition, even though there are many studies which relate it with a poor survival, its relation with toxicity has not yet been consistently reported. The aim of this study was to associate malnutrition and albumin serum levels with the occurrence of chemotherapy-induced toxicity in cisplatin plus paclitaxel chemotherapy-treated NSCLC.</p> <p>Methods</p> <p>We prospectively evaluated 100 stage IV NSCLC patients treated with paclitaxel (175 mg/m²) and cisplatin (80 mg/m²). Malnutrition was assessed using SGA prior treatment. Neutrophil Lymphocyte Ratio (NLR) and the Platelet Lymphocyte Ratio (PLR) were used to determine the presence of systemic inflammatory response (SIR) and were related to the development of toxicity. Toxicity was graded according to NCI CTCAE version 3.0 after two chemotherapy cycles.</p> <p>Results</p> <p>Median age was 58 ± 10 years, 51% of patients were malnourished, 50% had albumin ≤3.0 mg/mL. NLR ≥ 5 was associated with basal hypoalbuminemia (mean ranks, 55.7 vs. 39 p = 0.006), ECOG = 2 (47.2 vs. 55.4 p = 0.026) and PLR ≥ 150 were significantly related with a basal body mass index ≤20 (56.6 vs. 43.5; p = 0.02) and hypoalbuminemia (58.9 vs. 41.3; p = 0.02). Main toxicities observed after 2 cycles of chemotherapy were alopecia (84%), nausea (49%), neuropathy (46%), anemia (33%), lymphopenia (31%), and leukopenia (30%). Patients malnourished and with hypoalbuminemia developed more chemotherapy-induced toxicity overall when compared with those without malnutrition (31 vs 22; <it>p </it>= 0.02) and normal albumin (mean ranks, 62 vs 43; <it>p </it>= 0.002), respectively. Hypoalbuminemia was associated with anemia (56 vs 47; <it>p </it>= 0.05), fatigue (58 vs 46; <it>p </it>= 0.01), and appetite loss (57.1 vs 46.7; <it>p </it>= 0.004) compared with normal albumin. PLR ≥ 150 was related with the development of toxicity grade III/IV (59.27 vs. 47.03 p = 0.008) and anemia (37.9 vs 53.8 p = 0.004).</p> <p>Conclusion</p> <p>SIR parameters were associated with malnutrition, weight loss and hypoalbuminemia. Chemotherapy-induced toxicity in NSCLC patients treated with paclitaxel and cisplatin was associated with malnutrition and hypoalbuminemia. Early nutritional assessment and support might confer beneficial effects.</p

SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects.

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development

Reproduction and Feeding of the Electric Fish <i>Brachyhypopomus gauderio</i> (Gymnotiformes: Hypopomidae) and the Discussion of a Life History Pattern for Gymnotiforms from High Latitudes

<div><p>The reproductive biology and feeding habits of the electric fish <i>Brachyhypopomus gauderio</i> were studied. The species has seasonal reproductive behavior, with breeding occurring during the Southern Hemisphere spring and summer, and having a positive relation with the photoperiod variation. <i>Brachyhypopomus gauderio</i> was defined as a fractional spawner, with low relative fecundity and high first maturation size. Sexual dimorphism was registered, males undergoing hypertrophy of the distal portion of caudal filament. The results on reproductive biology herein obtained are in agreement with data concerning gymnotiforms from Southern Brazil and Uruguay, pointing to an ecological pattern for the species from high latitudes, differing from species with tropical distribution. According to the analysis of the food items, <i>B</i>. <i>gauderio</i> feed mainly on autochthonous insects, likewise the other gymnotiforms previously investigated, leading to conclude that there is no variation on the diet of the species of the order related to climatic conditions or even to habitat of occurrence.</p></div