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

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.

Citing Articles

Airway ciliary microenvironment responses in mice with primary ciliary dyskinesia and central pair apparatus defects.

McKenzie C, Wilcox R, Isaiah O, Kareta M, Lee L Sci Rep. 2024; 14(1):28437.

PMID: 39558053 PMC: 11574124. DOI: 10.1038/s41598-024-79877-z.

Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention.

Okada N, Oshima K, Maruko A, Sekine M, Ito N, Wakasugi A Front Psychiatry. 2024; 15:1450708.

PMID: 39364384 PMC: 11446786. DOI: 10.3389/fpsyt.2024.1450708.

Contribution of intraflagellar transport to compartmentalization and maintenance of the photoreceptor cell.

Lewis T, Castillo C, Klementieva N, Hsu Y, Hao Y, Spencer W Proc Natl Acad Sci U S A. 2024; 121(34):e2408551121.

PMID: 39145934 PMC: 11348033. DOI: 10.1073/pnas.2408551121.

Exploring the origins of neurodevelopmental proteasomopathies associated with cardiac malformations: are neural crest cells central to certain pathological mechanisms?.

Vignard V, Baruteau A, Toutain B, Mercier S, Isidor B, Redon R Front Cell Dev Biol. 2024; 12:1370905.

PMID: 39071803 PMC: 11272537. DOI: 10.3389/fcell.2024.1370905.

Case report of a child with nephronophthisis from South Africa.

Bhimma R, Jembere E, Hariparshad S BMC Pediatr. 2024; 24(1):431.

PMID: 38965466 PMC: 11225275. DOI: 10.1186/s12887-024-04872-2.

References

Chaki M, Hoefele J, Allen S, Ramaswami G, Janssen S, Bergmann C . Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies. Kidney Int. 2011; 80(11):1239-45. PMC: 4037742. DOI: 10.1038/ki.2011.284. View

Sun Z, Amsterdam A, Pazour G, Cole D, Miller M, Hopkins N . A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney. Development. 2004; 131(16):4085-93. DOI: 10.1242/dev.01240. View

Badano J, Mitsuma N, Beales P, Katsanis N . The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006; 7:125-48. DOI: 10.1146/annurev.genom.7.080505.115610. View

Nachury M, Loktev A, Zhang Q, Westlake C, Peranen J, Merdes A . A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell. 2007; 129(6):1201-13. DOI: 10.1016/j.cell.2007.03.053. View

Casteels I, Demandt E, Legius E . Visual loss as the presenting sign of Jeune syndrome. Eur J Paediatr Neurol. 2000; 4(5):243-7. DOI: 10.1053/ejpn.2000.0313. View

Thiel C, Kessler K, Giessl A, Dimmler A, Shalev S, von der Haar S . NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am J Hum Genet. 2011; 88(1):106-14. PMC: 3014367. DOI: 10.1016/j.ajhg.2010.12.004. View

Schmidts M, Frank V, Eisenberger T, Al Turki S, Bizet A, Antony D . Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease. Hum Mutat. 2013; 34(5):714-24. PMC: 4226634. DOI: 10.1002/humu.22294. View

Ruiz-Perez V, Ide S, Strom T, Lorenz B, Wilson D, Woods K . Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet. 2000; 24(3):283-6. DOI: 10.1038/73508. View

Schmidts M, Arts H, Bongers E, Yap Z, Oud M, Antony D . Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. J Med Genet. 2013; 50(5):309-23. PMC: 3627132. DOI: 10.1136/jmedgenet-2012-101284. View

10.

Beales P, Bland E, Tobin J, Bacchelli C, Tuysuz B, Hill J . IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet. 2007; 39(6):727-9. DOI: 10.1038/ng2038. View

11.

Huber C, Cormier-Daire V . Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet. 2012; 160C(3):165-74. DOI: 10.1002/ajmg.c.31336. View

12.

Czarnecki P, Shah J . The ciliary transition zone: from morphology and molecules to medicine. Trends Cell Biol. 2012; 22(4):201-10. PMC: 3331593. DOI: 10.1016/j.tcb.2012.02.001. View

13.

Dagoneau N, Goulet M, Genevieve D, Sznajer Y, Martinovic J, Smithson S . DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009; 84(5):706-11. PMC: 2681009. DOI: 10.1016/j.ajhg.2009.04.016. View

14.

Lehman A, Eydoux P, Doherty D, Glass I, Chitayat D, Chung B . Co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy. Am J Med Genet A. 2010; 152A(6):1411-9. PMC: 4048012. DOI: 10.1002/ajmg.a.33416. View

15.

Sang L, Miller J, Corbit K, Giles R, Brauer M, Otto E . Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell. 2011; 145(4):513-28. PMC: 3383065. DOI: 10.1016/j.cell.2011.04.019. View

16.

Pedersen L, Miller M, Geimer S, Leitch J, Rosenbaum J, Cole D . Chlamydomonas IFT172 is encoded by FLA11, interacts with CrEB1, and regulates IFT at the flagellar tip. Curr Biol. 2005; 15(3):262-6. DOI: 10.1016/j.cub.2005.01.037. View

17.

Davis E, Zhang Q, Liu Q, Diplas B, Davey L, Hartley J . TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011; 43(3):189-96. PMC: 3071301. DOI: 10.1038/ng.756. View

18.

Lunt S, Haynes T, Perkins B . Zebrafish ift57, ift88, and ift172 intraflagellar transport mutants disrupt cilia but do not affect hedgehog signaling. Dev Dyn. 2009; 238(7):1744-59. PMC: 2771627. DOI: 10.1002/dvdy.21999. View

19.

Baker K, Beales P . Making sense of cilia in disease: the human ciliopathies. Am J Med Genet C Semin Med Genet. 2009; 151C(4):281-95. DOI: 10.1002/ajmg.c.30231. View

20.

Halbritter J, Porath J, Diaz K, Braun D, Kohl S, Chaki M . Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet. 2013; 132(8):865-84. PMC: 4643834. DOI: 10.1007/s00439-013-1297-0. View