TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport.

Miriam Schmidts,Zhi Min Yap,Parthiban Vijayarangakannan,Stephen O’Rahilly,Mangino Massimo,Feng Zhang,Lorraine Southam,Ioanna Tachmazidou,Marie-Jo Brion,Aarno Palotie,Celia Greenwood,Rui Li,Gerome Breen,Mitali Patel,Steve E Humphries,Marta Futema,Sarah Metrustry,Jun Wang,Hannah M Mitchison,Scott G Wilson,Petr Danecek,Xiaosen Guo,Gail Clement,Jeremy Parr,George Davey Smith,Warren Herridge,Anja Kolb-Kokocinski,Daniel G Macarthur,J Brent Richards,Ellie Wheeler,Jamie Bentham,Shoumo Bhattacharya,Thomas Keane,Lavinia Paternoster,Peter Mcguffin,Jamie Floyd,S Paige Taylor,Yuqing Hou,Chris Boustred,Nic Timpson,Sue Ring,Alireza Moayyeri,Paul Flicek,Hou-Feng Zheng,Karsten Boldt,Peter Ellis,Alexandros Onoufriadis,Shane Mccarthy,Jeroen Van Reeuwijk,Yalda Jamshidi,Dinu Antony,Jennifer Asimit,Hugh Gurling,Margriet Van Kogelenberg,Mattia Calissano,Cordelia Langford,Michael A Quail,Margarida Lopes,Colin A Johnson,I Sadaf Farooqi,Victoria Parker,Gabriela Surdulescu,Dorus A Mans,Xu Changjiang,Sarah Curran,Karola Rehnström,Lydia Quaye,A Reghan Foley,David B Savage,Inês Barroso,Peter Clapham,Keren Carss,Irene Lee,Matt Hurles,Tamieka Whyte,Jean-Marc Plaza,Jonathan Marchini,Lucy Crooks,Lu Chen,Deborah Hart,Yingrui Li,Louise Gallagher,Stephen M King,Catherine Cosgrove,Sarah Edkins,Richard Durbin,Kate Northstone,Andrew Mckechanie,Detelina Grozeva,Krishna Chatterjee,Hywel Williams,Michael Owen,Ronald Roepman,Kathy Williamson,David Collier,David Jewell,Felicity Payne,Nicole Soranzo,David Skuse,David Jackson,Ghazaleh Fatemifar,Martin Bobrow,Karen Kennedy,Karim Oualkacha,Chris Franklin,Peter J Scambler,Jim Stalker,Marius Ueffing,Mohammad Ayub,Kalliope Panoutsopoulou,Robert K Semple,Vincent Plagnol,Alastair Kent,Carol Wicking,Eleftheria Zeggini,Dawn Muddyman,George B Witman,Guy Coates,Eva Serra,Jing Tian,Jaana Suvisaari,Sebhattin Cirak,Peter Holmans,Yasin Memari,Deborah Krakow,Jie Huang,John Perry,Claudio R Cortés,Artigas María Soler,Philip L Beales,Jouko Lönnqvist,John Maslen,Nick Craddock,Douglas Blackwood,James Morris,Sylvia E C Van Beersum,Lucy Raymond,Liu Ryan,Allan Daly,Ros Whittall,Tiina Paunio,Tony Cox,Richard Anney,Nadia Schoenmakers,Andrew Mcquillin,Saeed Al-Turki,Hashem A Shihab ,J F Kaye ,Elena G Bochukova ,David St Clair ,Josine L Min ,C Smee ,Andrew H Brown ,J M Barrett ,Hülya Kayserili ,John P Kemp ,Kerrin S Small ,David A Evans ,Michael Conlon O'donovan ,Andrew M Mcintosh ,F Muntoni ,Patrick B Bolton ,Audrey E Hendricks ,Daniel H Geschwind ,Tim D Spector ,Stef J.f Letteboer ,Beaté St Pourcain ,Ian N.m Day ,Aaron G Day‐Williams ,Ana M Valdes ,Martin D Tobin ,David R Fitzpatrick ,Louise V Wain ,Lihadh Al‐Gazali ,Valérie Cormier‐Daire ,Olli Pietiläinen ,So–Youn Shin ,Pirro G Hysi ,K Walter ,Geneviève Lachance ,Carl E Anderson ,J Janse Chris ,Kim Ping Wong ,Graham R S Ritchie ,K Ward ,Tom R Gaunt ,Céline Huber

doi:10.1038/ncomms8074

Abstract

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.

Highlights

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
Reverse transcription PCR (RT-PCR) on RNA derived from fibroblasts of UCL82 II.[1] detected no TCTEX1D2 transcript, suggesting nonsense-mediated decay (NMD) of the mutant transcript (Supplementary Fig. 2a)
Reverse transcription PCR on RNA derived from blood lymphocytes of individuals UCL4 II.[6] and II.[8] detected no TCTEX1D2 transcript, indicating likely NMD of the mutant transcript (Supplementary Fig. 2b), and no transcripts initiated at the TM4SF19 start codon continuing into TCTEX1D2 downstream of the deletion either

Summary

Introduction

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. Mutations in several IFT dynein components cause short-rib polydactyly syndromes (SRPS) and Jeune asphyxiating thoracic dystrophy (JATD; Jeune syndrome), a group of autosomal recessively inherited, genetically heterogeneous ciliary chondrodysplasias with overlapping phenotypic features[12,13,14,15,16]. Disease-causing mutations are considered hypomorphic since no individuals with SRPS or JATD were previously shown to carry biallelic loss-of-function mutations[13,17], and homozygosity for ‘null’ alleles is embryonic lethal in mouse models around midgestation[25,26]. We report biallelic loss-of-function mutations causing JATD in the gene encoding TCTEX1D2, an IFT dynein light chain distinct from DYNLL1/DYNLL2 (LC8). Compared with mutations in other IFT dynein components, TCTEX1D2/Tctex2b loss in human, zebrafish and Chlamydomonas has a modest effect on retrograde IFT, likely explaining the partially penetrant nature of human TCTEX1D2 mutations

Methods

Results

Conclusion