Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans.


Journal Article

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.

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Cited Authors

  • Halbritter, J; Bizet, AA; Schmidts, M; Porath, JD; Braun, DA; Gee, HY; McInerney-Leo, AM; Krug, P; Filhol, E; Davis, EE; Airik, R; Czarnecki, PG; Lehman, AM; Trnka, P; Nitschké, P; Bole-Feysot, C; Schueler, M; Knebelmann, B; Burtey, S; Szabó, AJ; Tory, K; Leo, PJ; Gardiner, B; McKenzie, FA; Zankl, A; Brown, MA; Hartley, JL; Maher, ER; Li, C; Leroux, MR; Scambler, PJ; Zhan, SH; Jones, SJ; Kayserili, H; Tuysuz, B; Moorani, KN; Constantinescu, A; Krantz, ID; Kaplan, BS; Shah, JV; UK10K Consortium, ; Hurd, TW; Doherty, D; Katsanis, N; Duncan, EL; Otto, EA; Beales, PL; Mitchison, HM; Saunier, S; Hildebrandt, F

Published Date

  • November 7, 2013

Published In

Volume / Issue

  • 93 / 5

Start / End Page

  • 915 - 925

PubMed ID

  • 24140113

Pubmed Central ID

  • 24140113

Electronic International Standard Serial Number (EISSN)

  • 1537-6605

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2013.09.012


  • eng

Conference Location

  • United States