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

Abstract: 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 caus- ative loci, a common molecular mechanism of cartilage defects and cystic kidneys has remained elusive. Targeting two ciliary chondro- dysplasia 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 estab- lished 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

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Proceedings of the National Academy of Sciences of the United States of America. - 118, 39 (2021) , e2106770118, ISSN: 1091-6490

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2021
• Creator: Getwan, Maike ; Hoppmann, Anselm ; Schlosser, Pascal ; Grand, Kelli ; Song, Weiting ; Diehl, Rebecca ; Schroda, Sophie ; Heeg, Florian ; Deutsch, Konstantin ; Hildebrandt, Friedhelm ; Lausch, Ekkehart ; Köttgen, Anna ; Lienkamp, Soeren

Further information

• DOI: 10.1073/pnas.2106770118
• URN: urn:nbn:de:bsz:25-freidok-2214768
• Rights: Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:45 PM CET