Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease.
Maike GetwanAnselm HoppmannPascal SchlosserKelli GrandWeiting SongRebecca DiehlSophie SchrodaFlorian HeegKonstantin DeutschFriedhelm HildebrandtEkkehart LauschAnna KöttgenSoeren Sten LienkampPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- crispr cas
- genome wide
- genome editing
- single cell
- end stage renal disease
- case report
- ejection fraction
- high throughput
- newly diagnosed
- polycystic kidney disease
- chronic kidney disease
- dna methylation
- cancer therapy
- lymph node
- electronic health record
- copy number
- drug delivery
- high resolution
- early onset
- machine learning
- bioinformatics analysis
- patient reported outcomes
- genome wide association
- convolutional neural network
- mass spectrometry
- climate change
- genome wide identification
- genome wide analysis
- nucleic acid
- transcription factor