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Proc Natl Acad Sci U S A 2021 Sep 28;11839:. doi: 10.1073/pnas.2106770118.
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Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease.

Getwan M , Hoppmann A , Schlosser P , Grand K , Song W , Diehl R , Schroda S , Heeg F , Deutsch K , Hildebrandt F , Lausch E , Köttgen A , Lienkamp SS .

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.

PubMed ID: 34548398
PMC ID: PMC8488674
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus tropicalis Xenopus laevis
Genes referenced: abcb1 aplnr c3ar1 cacng1 ccng1 cep192 cfap20 cfh col1a1 col2a1 dscaml1 emb gli1 gli2 ift172 ift70a ift80 iftap kif17 nkx2-2 nkx2-5 olfm4 pam pax2 pitx2 prmt9 prox1 ptch1 riok3 shh slc12a1 slc45a2 slc5a1.2 slc5a9 snai1 snai2 sox9 twist1 ulk1 XB5809687 zic1
GO keywords: kidney development [+]
Antibodies: Tuba4b Ab4
Morpholinos: ift172 MO1 ift80 MO1
gRNAs referenced: ift172 gRNA1 ift70a gRNA1 ift80 gRNA1

Disease Ontology terms: cranioectodermal dysplasia [+]
Phenotypes: Xla Wt + ift172 CRISPR (Sup. Fig. 1 e) [+]

Article Images: [+] show captions
References [+] :
Alby, Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome. 2015, Pubmed