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.

骨骼纤毛病（例如，Jeune 综合征、短肋多指综合征和 Sensenbrenner 综合征）经常与肾癣样囊性肾病和其他器官表现有关。尽管最近在致病基因座的遗传定位方面取得了进展，但软骨缺损和囊性肾的常见分子机制仍然难以捉摸。通过 CRISPR/Cas9 诱变靶向两个纤毛软骨发育不良基因座（ift80和ift172），我们建立了热带非洲爪蟾骨骼纤毛病的模型。青蛙表现出严重的四肢畸形、多指畸形和囊性肾脏，与受影响患者的表型密切匹配。基于数据挖掘的计算机屏幕发现ttc30a与已知的骨骼纤毛病基因有关。CRISPR/Cas9 靶向复制的肢体畸形和肾囊肿，与已建立的疾病基因模型相同。由于翻译后微管蛋白乙酰化、糖基化和轴丝区室化缺陷的改变，Ttc30a 的缺失会损害胚胎肾排泄和纤毛发生。Ttc30a/b转录物富含单细胞 RNA 测序的胚胎小鼠四肢的软骨细胞和骨细胞。我们将 TTC30A/B 确定为纤毛软骨发育不良和肾癣样疾病蛋白网络中的重要节点，并表明微管蛋白修饰和纤毛分割以细胞类型特异性方式导致纤毛病的骨骼和肾纤毛病表现。这些发现对潜在的治疗策略有影响。