Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans

Halbritter, Jan, Bizet, Albane A., Schmidts, Miriam, Porath, Jonathan D., Braun, Daniela A., Gee, Heon Yung, McInerney-Leo, Aideen M., Krug, Pauline, Filhol, Emilie, Davis, Erica E., Airik, Rannar, Czarnecki, Peter G., Lehman, Anna M., Trnka, Peter, Nitschke, Patrick, Bole-Feysot, Christine, Schueler, Markus, Knebelmann, Bertrand, Burtey, Stephane, Szabo, Attila J., Tory, Kalman, Leo, Paul J., Gardiner, Brooke, McKenzie, Fiona A., Zankl, Andreas, Brown, Matthew A., Hartley, Jane L., Maher, Eamonn R., Li, Chunmei, Leroux, Michel R., Scambler, Peter J., Zhan, Shing H., Jones, Steven J., Kayserili, Hulya, Tuysuz, Beyhan, Moorani, Khemchand N., Constantinescu, Alexandru, Krantz, Ian D., Kaplan, Bernard S., Shah, Jagesh V., Hurd, Toby W., Doherty, Dan, Katsanis, Nicholas, Duncan, Emma L., Otto, Edgar A., Beales, Philip L., Mitchison, Hannah M., Saunier, Sophie and Hildebrandt, Friedhelm (2013) Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans. American Journal of Human Genetics, 93 5: 915-925. doi:10.1016/j.ajhg.2013.09.012

Author Halbritter, Jan
Bizet, Albane A.
Schmidts, Miriam
Porath, Jonathan D.
Braun, Daniela A.
Gee, Heon Yung
McInerney-Leo, Aideen M.
Krug, Pauline
Filhol, Emilie
Davis, Erica E.
Airik, Rannar
Czarnecki, Peter G.
Lehman, Anna M.
Trnka, Peter
Nitschke, Patrick
Bole-Feysot, Christine
Schueler, Markus
Knebelmann, Bertrand
Burtey, Stephane
Szabo, Attila J.
Tory, Kalman
Leo, Paul J.
Gardiner, Brooke
McKenzie, Fiona A.
Zankl, Andreas
Brown, Matthew A.
Hartley, Jane L.
Maher, Eamonn R.
Li, Chunmei
Leroux, Michel R.
Scambler, Peter J.
Zhan, Shing H.
Jones, Steven J.
Kayserili, Hulya
Tuysuz, Beyhan
Moorani, Khemchand N.
Constantinescu, Alexandru
Krantz, Ian D.
Kaplan, Bernard S.
Shah, Jagesh V.
Hurd, Toby W.
Doherty, Dan
Katsanis, Nicholas
Duncan, Emma L.
Otto, Edgar A.
Beales, Philip L.
Mitchison, Hannah M.
Saunier, Sophie
Hildebrandt, Friedhelm
Title Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
Publication date 2013-11-01
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2013.09.012
Volume 93
Issue 5
Start page 915
End page 925
Total pages 11
Place of publication Cambridge, United States
Publisher Cell Press
Language eng
Formatted abstract
Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.
Keyword Asphyxiating Thoracic Dystrophy
Intraflagellar Transport Protein
Rib-Polydactyly Syndrome
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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