Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease.

Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic kidney disease and other organ manifestations. Despite recent progress in genetic mapping of causative loci, a common molecular mechanism of cartilage defects and cystic kidneys has remained elusive. Targeting two ciliary chondrodysplasia loci (ift80 and ift172) by CRISPR/Cas9 mutagenesis, we established models for skeletal ciliopathies in Xenopus tropicalis Froglets exhibited severe limb deformities, polydactyly, and cystic kidneys, closely matching the phenotype of affected patients. A data mining-based in silico screen found ttc30a to be related to known skeletal ciliopathy genes. CRISPR/Cas9 targeting replicated limb malformations and renal cysts identical to the models of established disease genes. Loss of Ttc30a impaired embryonic renal excretion and ciliogenesis because of altered posttranslational tubulin acetylation, glycylation, and defective axoneme compartmentalization. Ttc30a/b transcripts are enriched in chondrocytes and osteocytes of single-cell RNA-sequenced embryonic mouse limbs. We identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins and suggest that tubulin modifications and cilia segmentation contribute to skeletal and renal ciliopathy manifestations of ciliopathies in a cell type-specific manner. These findings have implications for potential therapeutic strategies.

TEMPORAL LINKS BETWEEN ENDOTOXIN ACTIVITY LEVELS AND INTERLEUKIN 6 CONCENTRATIONS IN ABDOMINAL SEPSIS.

In severe human peritonitis, the precise pathophysiological importance of endotoxin is controversial. Prognostic and therapeutic studies have yielded conflicting results. The current study wanted to investigate qualitative, quantitative, and temporal associations between blood endotoxin activity (EA) levels and acute inflammatory reactions. We conducted a prospective observational study in 30 patients with intra-abdominal infections who had undergone specific focus therapies (surgical/radiological/pharmaceutical interventions) and who required intensive care therapy. We performed sequential postinterventional measurements of blood EA levels and plasma interleukin 6 (IL-6) concentrations until recurrence or cure. There was no association between daily EA levels and IL-6 concentrations, or daily EA levels and changes in IL-6 concentrations on subsequent days. We found, however, a significant association between EA levels and IL-6 concentrations, when newly changing EA levels were referred to subsequent changes in IL-6 concentrations (P < 0.05). Increasing EA levels were followed by a 90% increase of subsequent IL-6 concentrations during the next 24 to 48 h, whereas decreasing/stable EA levels were associated with slightly decreasing IL-6 concentrations (P < 0.05). Our findings suggest an altered response of the innate immune system because postinterventional EA levels did not vary with concomitant or subsequent inflammatory reactions and because inflammatory responses to newly increasing EA levels were delayed and comparatively small. Still, our results support the concept that endotoxin is a trigger of inflammatory reactions in human peritonitis.