Congenital anomalies of the urinary system (CAKUT) are one of the most common causes of chronic kidney disease in children. To date, over 180 genes have been identified whose mutations have been associated with CAKUT, but these only account for 10% of cases. This suggests that there are many more genes that cause CAKUT.
DNA samples of 3 siblings with CAKUT (two of them twin) from a consanguineous family who were identified at Department of Pediatric Nephrology in İstanbul University-Cerrahpaşa were sent to the Nephrogenetics Laboratory of Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine for genetic studies.Whole exome sequencing was performed using these DNA samples by Professor Fatih Özaltın and his team. A homozygous variant in TBC1D31 gene that is segregated with the disease in the family was identified. Its pathogenicity was revealed by molecular dynamics simulations that was critically performed by Professor Turgut Baştuğ from Department of Biophysics, Hacettepe University Faculty of Medicine. It was concluded that the detected variant changed the 3D structure of the protein and disrupted the atomic interactions between amino acids. TBC1D31 protein is present in the cilia structure, which is known to have a very important role in organogenesis. It is expressed in centrosome and pericentrolar satellites and has been conserved throughout evolution in higher organisms. Previous studies have shown that TBC1D31 is responsible for assembly of the E3 ubiquitin ligase praja2, the complex that includes protein kinase A. OFD1 is also involved in this complex, and its phosphorylation by protein kinase A occurs in the TBC1D31/praja2 complex in the centrosome, causing proteolysis of OFD1 by the praja2-ubiquitin-proteasome system (UPS). The initiation of ciliogenesis also begins with the selective removal of OFD1 from the pericentrolar area by autophagy. Any abnormality that disrupts these mechanisms results in reduced cilia number and length, which is one of the mechanisms involved in the pathogenesis of CAKUT. Therefore, in our study, the TBC1D31 variant in the aforementioned complex was thought to be associated with the CAKUT phenotype for the first time, thus contributing to a better understanding of the pathogenesis of CAKUT while expanding its genetic spectrum.
This study was published online in the journal Clinical Genetics in July 2023. (https://pubmed.ncbi.nlm.nih.gov/37468454/)
