TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport.
Schmidts M., Hou Y., Cortés CR., Mans DA., Huber C., Boldt K., Patel M., van Reeuwijk J., Plaza J-M., van Beersum SEC., Yap ZM., Letteboer SJF., Taylor SP., Herridge W., Johnson CA., Scambler PJ., Ueffing M., Kayserili H., Krakow D., King SM., UK10K None., Beales PL., Al-Gazali L., Wicking C., Cormier-Daire V., Roepman R., Mitchison HM., Witman GB.
The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.