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Ttc30a affects tubulin modifications in a model for ciliary chondrodysplasia with polycystic kidney disease
Maike Getwan1,2,3, Anselm Hoppmann4, Pascal Schlosser4
1Institute of Anatomy, University of Zurich, 8057 Zurich, Switzerland.
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 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.
Insights
Researchers identified TTC30A/B as a key protein in skeletal ciliopathies and cystic kidney disease. Loss of TTC30A causes limb deformities and kidney issues by affecting cilia function, offering insights into disease mechanisms.
Area of Science:
- Genetics and Molecular Biology
- Developmental Biology
- Nephrology
Background:
- Skeletal ciliopathies, including Jeune syndrome and short rib polydactyly syndrome, often involve cystic kidney disease and other organ issues.
- The common molecular basis for cartilage defects and cystic kidneys in these ciliopathies remains unclear despite advances in genetic mapping.
Purpose of the Study:
- To investigate the molecular mechanisms underlying skeletal ciliopathies and associated nephronophthisis-like kidney disease.
- To identify novel genes and pathways involved in ciliogenesis and organ development relevant to these conditions.
Main Methods:
- Generated Xenopus tropicalis models for skeletal ciliopathies using CRISPR/Cas9 targeting of ciliary chondrodysplasia loci (ift80, ift172).
- Utilized in silico screening to identify TTC30A as a potential disease-related gene and validated its role via CRISPR/Cas9 mutagenesis in Xenopus.
- Analyzed the impact of Ttc30a loss on embryonic renal excretion, ciliogenesis, tubulin posttranslational modifications, and axoneme structure; examined Ttc30a/b expression in mouse embryos.
Main Results:
- Xenopus models recapitulated key features of skeletal ciliopathies, including limb deformities and cystic kidneys.
- CRISPR/Cas9 targeting of ttc30a in Xenopus replicated the disease phenotype, highlighting its role in skeletal and renal development.
- Loss of Ttc30a disrupted renal excretion and ciliogenesis, linked to altered tubulin acetylation/glycylation and defective axoneme compartmentalization; Ttc30a/b are expressed in chondrocytes and osteocytes.
Conclusions:
- TTC30A/B is identified as a crucial protein in the network connecting ciliary chondrodysplasia and nephronophthisis-like kidney disease.
- Tubulin modifications and cilia segmentation are implicated as key contributors to skeletal and renal ciliopathy manifestations in a cell-type-specific manner.
- These findings provide a foundation for exploring novel therapeutic strategies for skeletal and renal ciliopathies.
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