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

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.

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IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy

Nature Genetics ◽

10.1038/ng2038 ◽

2007 ◽

Vol 39 (6) ◽

pp. 727-729 ◽

Cited By ~ 230

Author(s):

Philip L Beales ◽

Elizabeth Bland ◽

Jonathan L Tobin ◽

Chiara Bacchelli ◽

Beyhan Tuysuz ◽

...

Keyword(s):

Intraflagellar Transport ◽

Transport Protein ◽

Asphyxiating Thoracic Dystrophy ◽

Thoracic Dystrophy

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Faculty Opinions recommendation of IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1086836.540864 ◽

2007 ◽

Author(s):

Sue Malcolm

Keyword(s):

Intraflagellar Transport ◽

Transport Protein ◽

Asphyxiating Thoracic Dystrophy ◽

Thoracic Dystrophy

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Faculty Opinions recommendation of IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1086836.539763 ◽

2007 ◽

Author(s):

Jane Hewitt

Keyword(s):

Intraflagellar Transport ◽

Transport Protein ◽

Asphyxiating Thoracic Dystrophy ◽

Thoracic Dystrophy

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The Intraflagellar Transport Protein Ift80 Is Essential for Photoreceptor Survival in a Zebrafish Model of Jeune Asphyxiating Thoracic Dystrophy

Investigative Ophthalmology & Visual Science ◽

10.1167/iovs.09-4312 ◽

2010 ◽

Vol 51 (7) ◽

pp. 3792-3799 ◽

Cited By ~ 26

Author(s):

L. M. Hudak ◽

S. Lunt ◽

C.-H. Chang ◽

E. Winkler ◽

H. Flammer ◽

...

Keyword(s):

Intraflagellar Transport ◽

Transport Protein ◽

Zebrafish Model ◽

Asphyxiating Thoracic Dystrophy ◽

Thoracic Dystrophy

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Faculty Opinions recommendation of IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1086836.543137 ◽

2007 ◽

Author(s):

Michael Briggs

Keyword(s):

Intraflagellar Transport ◽

Transport Protein ◽

Asphyxiating Thoracic Dystrophy ◽

Thoracic Dystrophy

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Interactions of LC8 with N-Terminal Segments of the Intermediate Chain of Cytoplasmic Dynein

The Scientific World JOURNAL ◽

10.1100/tsw.2003.56 ◽

2003 ◽

Vol 3 ◽

pp. 647-654 ◽

Cited By ~ 2

Author(s):

Afua Nyarko ◽

Michael Hare ◽

Moses Makokha ◽

Elisar Barbar

Keyword(s):

Limited Proteolysis ◽

Coiled Coil ◽

Cytoplasmic Dynein ◽

Light Chains ◽

Ordered Structure ◽

Dynein Motor ◽

Dynein Light Chains ◽

Significant Conformational Change ◽

Intermediate Chain

LC8, a highly conserved 10-kDa light chain, and IC74, a 74-kDa intermediate chain, are presumed to promote the assembly of the cytoplasmic dynein motor protein complex and to be engaged in the controlled binding and release of cargo. The interactions of LC8 from Drosophila melanogaster with constructs of IC74 were characterized in vitro by affinity methods, limited proteolysis, and circular dichroism spectroscopy. Previously, we have performed limited proteolysis on the N-terminal domain of IC74, IC(1-289), when free and when bound to dynein light chains LC8 and Tctex-1[1]. We have also shown that upon addition of LC8, IC(1-289) undergoes a significant conformational change from a largely unfolded to a more ordered structure. The purpose of the work presented here is to determine whether residues 1-30 in IC74, predicted to be in a coiled coil, are involved in the stabilization of the protein upon binding to LC8. Constructs of IC74, IC(1-143), and IC(30-143) that include the LC8 binding site but with and without the first 30 residues were prepared, and their binding and protection patterns were compared to our previous results for IC(1-289). The results suggest that coiled coil residues 1-30 are not responsible for the increase in structure we observe when IC(1-289) binds to LC8.

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