Functional characterization of tektin-1 in motile cilia and evidence for TEKT1 as a new candidate gene for motile ciliopathies

Abstract

A child presenting with Mainzer-Saldino syndrome (MZSDS), characterized by renal, retinal and skeletal involvements, was also diagnosed with lung infections and airway ciliary dyskinesia. These manifestations suggested dysfunction of both primary and motile cilia, respectively. Targeted exome sequencing identified biallelic mutations in WDR19, encoding an IFT-A subunit previously associated with MZSDS-related chondrodysplasia, Jeune asphyxiating thoracic dysplasia and cranioectodermal dysplasia, linked to primary cilia dysfunction, and in TEKT1 which encodes tektin-1 an uncharacterized member of the tektin family, mutations of which may cause ciliary dyskinesia. Tektin-1 localizes at the centrosome in cycling cells, at basal bodies of both primary and motile cilia and to the axoneme of motile cilia in airway cells. The identified mutations impaired these localizations. In addition, airway cells from the affected individual showed severe motility defects without major ultrastructural changes. Knockdown of tekt1 in zebrafish resulted in phenotypes consistent with a function for tektin-1 in ciliary motility, which was confirmed by live imaging. Finally, experiments in the zebrafish also revealed a synergistic effect of tekt1 and wdr19. Altogether, our data show genetic interactions between WDR19 and TEKT1 likely contributing to the overall clinical phenotype observed in the affected individual and provide strong evidence for TEKT1 as a new candidate gene for primary ciliary dyskinesia.

Tubulin lattice in cilia is in a stressed form regulated by microtubule inner proteins

“…All these MIPs mentioned above are conserved in humans (14). Mutations in homologs of tektin, Rib72, and FAP52 are associated with diseases in humans (15)(16)(17). Therefore, the MIPs must be important for the motility and stability of the cilia.…”

Rare Human Diseases: Model Organisms in Deciphering the Molecular Basis of Primary Ciliary Dyskinesia

“…The exon-enriched NGS led to the identification of the mutations in two genes: (1) WDR19, encoding the intraflagellar transport component IFT144, known to be associated with ciliopathies caused by the improper function of the primary cilia [242]; and (2) TEKT1, which earlier was not associated with ciliopathies. Tektin-1 localizes to the centrosome, basal bodies, and along the motile cilia axoneme, but not in the primary cilia [223].…”

“…The whole-exome or genome sequencing of samples obtained from the individuals with clinical features consistent with PCD led to the identification of mutations in additional loci, and thus additional likely PCD-related genes. Among them are GAS2L2 (growth arrest-specific protein 2-like 2) [218], OFD1 [219,220], RPGR [221,222], and possibly TEKT1 [223] and LRRC56 [224].…”

“…Recently, a case of a patient was reported, who, besides having symptoms typical for Mainzer-Saldino syndrome (MZSDS) such as nephronophthisis, retinal dystrophy and skeletal abnormalities [241], also suffered from recurrent airway infections [223]. The HSVM analyses of the cells obtained from nasal brushing revealed that the number of cilia was significantly reduced, and assembled cilia were either immotile or beat with a reduced amplitude and with very low frequency [223]. The TEM studies showed that basal bodies in the analysed multiciliated cells were misoriented, while ciliary axonemes seemed to have a normal ultrastructure [223].…”

“…The HSVM analyses of the cells obtained from nasal brushing revealed that the number of cilia was significantly reduced, and assembled cilia were either immotile or beat with a reduced amplitude and with very low frequency [223]. The TEM studies showed that basal bodies in the analysed multiciliated cells were misoriented, while ciliary axonemes seemed to have a normal ultrastructure [223]. The exon-enriched NGS led to the identification of the mutations in two genes: (1) WDR19, encoding the intraflagellar transport component IFT144, known to be associated with ciliopathies caused by the improper function of the primary cilia [242]; and (2) TEKT1, which earlier was not associated with ciliopathies.…”