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

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.

Sensenbrenner Syndrome Presenting with Severe Anorexia, Failure to Thrive, Chronic Kidney Disease and Angel-Shaped Middle Phalanges in Two Siblings

Sensenbrenner syndrome is a very rare autosomal recessive disorder caused by variants in genes involved in the functional development of primary cilia. Typical clinical manifestations include craniofacial and skeletal abnormalities, hence the alternative name cranioectodermal dysplasia. Chronic kidney disease due to progressive tubulointerstitial nephritis (nephronophthisis) has been described in these patients. The authors present 2siblings with severe anorexia, failure to thrive, chronic kidney disease, and angel-shaped middle phalanges. Two previously described variants p.(Leu641*) and p.(Asp841Val) were identified in the <i>WDR35</i> gene which is most commonly affected in this condition. Analysis of all coding exons of the <i>GDF5</i> gene was normal. This is the first report of Sensenbrenner syndrome presenting with severe anorexia and failure to thrive at early age. Angel-shaped middle phalanges in the absence of the <i>GDF5</i> variant may represent an overlapping phenotypic manifestation of ciliopathy.

Non-traumatic epidural posterior fossa hematomas in child with Sensenbrenner syndrome: a case report and literature review

Background: Posterior fossa extradural hematomas are an uncommon condition with more than half of cases appearing in the pediatric population. Although the majority of cases are caused by substantial trauma, it may also be related to systemic diseases and bleeding disorders without the history of head trauma. Case report: We present the case of a 6-year-old female affected by Sensenbrenner syndrome with a non-traumatic subacute posterior fossa epidural hematoma. The patient was surgically treated and medically discharged without further neurological alteration. This is the first report of spontaneous cerebral hematoma associated with this syndrome in the literature. A literature review of the main aspects of both topics was performed. Conclusions: Although spontaneous posterior fossa epidural hematomas are rare, clinicians should be aware and highly suspicious of this differential diagnosis in certain situations such as coagulopathies and other specific systemic diseases, as fast recognition and assertive treatment are important for better outcomes.

CRISPR/Cas9 targeting Ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease

Skeletal ciliopathies (e.g. Jeune syndrome, short rib polydactyly syndrome, Sensenbrenner syndrome) are frequently associated with cystic kidney disease and other organ manifestations, but a common molecular mechanism has remained elusive.We established two models for skeletal ciliopathies (ift80 and ift172) in Xenopus tropicalis, which exhibited severe limb deformities, polydactyly, cystic kidneys, and ciliogenesis defects, closely matching the phenotype of affected patients.Employing data-mining and an in silico screen we identified candidate genes with similar molecular properties to genetically validated skeletal ciliopathy genes. Among four genes experimentally validated, CRISPR/Cas9 targeting of ttc30a replicated all aspects of the phenotypes observed in the models of genetically confirmed disease genes, including ciliary defects, limb deformations and cystic kidney disease.Our findings establish three new models for skeletal ciliopathies (ift80, ift172, ttc30a) and identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins implicating post-translational tubulin modifications in its pathogenesis.