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Skeletal ciliopathy: pathogenesis and related signaling pathways

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Abstract

Cilia are tiny organelles with conserved structures and components in eukaryotic cells. Ciliopathy is a set of diseases resulting from cilium dysfunction classified into first-order and second-order ciliopathy. With the advancement of clinical diagnosis and radiography, numerous skeletal phenotypes, including polydactyly, short limbs, short ribs, scoliosis, a narrow thorax, and numerous anomalies in bone and cartilage, have been discovered in ciliopathies. Mutation in genes encoding cilia core components or other cilia-related molecules have been found in skeletal ciliopathies. Meanwhile, various signaling pathways associated with cilia and skeleton development have been deemed to be significant for the occurrence and progression of diseases. Herein, we review the structure and key components of the cilium and summarize several skeletal ciliopathies with their presumable pathology. We also emphasize the signaling pathways involved in skeletal ciliopathies, which may assist in developing potential therapies for these diseases.

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References

  1. Malicki JJ, Johnson CA (2017) The cilium: cellular antenna and central processing unit. Trends Cell Biol 27(2):126–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Reiter JF, Leroux MR (2017) Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol 18(9):533–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Goetz SC, Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11(5):331–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hildebrandt F, Benzing T, Katsanis N (2011) Ciliopathies. N Engl J Med 364(16):1533–1543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Saito M, Hirano M, Izumi T, Mori Y, Ito K, Saitoh Y, Terada N, Sato T, Sukegawa J (2022) Cytoskeletal protein 4.1G is essential for the primary ciliogenesis and osteoblast differentiation in bone formation. Int J Mol Sci 23(4):2094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Coveney CR, Zhu L, Miotla-Zarebska J, Stott B, Parisi I, Batchelor V, Duarte C, Chang E, McSorley E, Vincent TL et al (2022) Role of ciliary protein intraflagellar transport protein 88 in the regulation of cartilage thickness and osteoarthritis development in mice. Arthritis Rheumatol 74(1):49–59

    Article  CAS  PubMed  Google Scholar 

  7. Bosakova M, Abraham SP, Nita A, Hruba E, Buchtova M, Taylor SP, Duran I, Martin J, Svozilova K, Barta T et al (2020) Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling. EMBO Mol Med 12(11):e11739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Moore ER, Jacobs CR (2018) The primary cilium as a signaling nexus for growth plate function and subsequent skeletal development. J Orthop Res 36(2):533–545

    Article  PubMed  Google Scholar 

  9. Reiter JF, Blacque OE, Leroux MR (2012) The base of the cilium: roles for transition fibres and the transition zone in ciliary formation, maintenance and compartmentalization. EMBO Rep 13(7):608–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Roosing S, Romani M, Isrie M, Rosti RO, Micalizzi A, Musaev D, Mazza T, Al-Gazali L, Altunoglu U, Boltshauser E et al (2016) Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes. J Med Genet 53(9):608–615

    Article  CAS  PubMed  Google Scholar 

  11. Cortes CR, McInerney-Leo AM, Vogel I, Rondon Galeano MC, Leo PJ, Harris JE, Anderson LK, Keith PA, Brown MA, Ramsing M et al (2016) Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function. Sci Rep 6:24083

    Article  PubMed  PubMed Central  Google Scholar 

  12. Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, Bialas NJ, Stupay RM, Chen N, Blacque OE et al (2011) MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol 192(6):1023–1041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Symoens S, Barnes AM, Gistelinck C, Malfait F, Guillemyn B, Steyaert W, Syx D, D’Hondt S, Biervliet M, De Backer J et al (2015) Genetic defects in TAPT1 disrupt ciliogenesis and cause a complex lethal osteochondrodysplasia. Am J Hum Genet 97(4):521–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ishikawa H, Marshall WF (2011) Ciliogenesis: building the cell’s antenna. Nat Rev Mol Cell Biol 12(4):222–234

    Article  CAS  PubMed  Google Scholar 

  15. Fisch C, Dupuis-Williams P (2011) Ultrastructure of cilia and flagella—back to the future! Biol Cell 103(6):249–270

    Article  PubMed  Google Scholar 

  16. Damerla RR, Cui C, Gabriel GC, Liu X, Craige B, Gibbs BC, Francis R, Li Y, Chatterjee B, San Agustin JT et al (2015) Novel Jbts17 mutant mouse model of Joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies. Hum Mol Genet 24(14):3994–4005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cela P, Hampl M, Shylo NA, Christopher KJ, Kavkova M, Landova M, Zikmund T, Weatherbee SD, Kaiser J, Buchtova M (2018) Ciliopathy protein Tmem107 plays multiple roles in craniofacial development. J Dent Res 97(1):108–117

    Article  CAS  PubMed  Google Scholar 

  18. Serra R (2008) Role of intraflagellar transport and primary cilia in skeletal development. Anat Rec (Hoboken) 291(9):1049–1061

    Article  CAS  PubMed  Google Scholar 

  19. Temiyasathit S, Tang WJ, Leucht P, Anderson CT, Monica SD, Castillo AB, Helms JA, Stearns T, Jacobs CR (2012) Mechanosensing by the primary cilium: deletion of Kif3A reduces bone formation due to loading. PLoS ONE 7(3):e33368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nakayama K, Katoh Y (2020) Architecture of the IFT ciliary trafficking machinery and interplay between its components. Crit Rev Biochem Mol Biol 55(2):179–196

    Article  CAS  PubMed  Google Scholar 

  21. Jin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, Bazan JF, Nachury MV (2010) The conserved Bardet–Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141(7):1208–1219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ye F, Nager AR, Nachury MV (2018) BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone. J Cell Biol 217(5):1847–1868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Baujat G, Le Merrer M (2007) Ellis–van Creveld syndrome. Orphanet J Rare Dis 2:27

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ruiz-Perez VL, Ide SE, Strom TM, Lorenz B, Wilson D, Woods K, King L, Francomano C, Freisinger P, Spranger S et al (2000) Mutations in a new gene in Ellis–van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 24(3):283–286

    Article  CAS  PubMed  Google Scholar 

  25. Louie KW, Mishina Y, Zhang H (2020) Molecular and cellular pathogenesis of Ellis–van Creveld syndrome: lessons from targeted and natural mutations in animal models. J Dev Biol 8(4):25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ruiz-Perez VL, Blair HJ, Rodriguez-Andres ME, Blanco MJ, Wilson A, Liu YN, Miles C, Peters H, Goodship JA (2007) EVC is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia. Development 134(16):2903–2912

    Article  CAS  PubMed  Google Scholar 

  27. Zhang H, Kamiya N, Tsuji T, Takeda H, Scott G, Rajderkar S, Ray MK, Mochida Y, Allen B, Lefebvre V et al (2016) Elevated fibroblast growth factor signaling is critical for the pathogenesis of the dwarfism in Evc2/Limbin mutant mice. PLoS Genet 12(12):e1006510

    Article  PubMed  PubMed Central  Google Scholar 

  28. Martinez-Frias ML, Bermejo E, Urioste M, Egues J, Lopez Soler JA (1993) Short rib-polydactyly syndrome (SRPS) with anencephaly and other central nervous system anomalies: a new type of SRPS or a more severe expression of a known SRPS entity? Am J Med Genet 47(5):782–787

    Article  CAS  PubMed  Google Scholar 

  29. Li C, Zheng Y, Zheng Y, Xu Z (2021) SRPS associated protein WDR60 regulates the multipolar-to-bipolar transition of migrating neurons during cortical development. Cell Death Dis 12(1):75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. McInerney-Leo AM, Schmidts M, Cortes CR, Leo PJ, Gener B, Courtney AD, Gardiner B, Harris JA, Lu Y, Marshall M et al (2013) Short-rib polydactyly and Jeune syndromes are caused by mutations in WDR60. Am J Hum Genet 93(3):515–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gholkar AA, Senese S, Lo YC, Capri J, Deardorff WJ, Dharmarajan H, Contreras E, Hodara E, Whitelegge JP, Jackson PK et al (2015) Tctex1d2 associates with short-rib polydactyly syndrome proteins and is required for ciliogenesis. Cell Cycle 14(7):1116–1125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Badiner N, Taylor SP, Forlenza K, Lachman RS, University of Washington Center for Mendelian Group, Bamshad M, Nickerson D, Cohn DH, Krakow D (2017) Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino–Noonan type. Clin Genet 92(2):158–165

  33. Zhang X, You Y, Xie X, Xu H, Zhou H, Lei Y, Sun P, Meng Y, Wang L, Lu Y (2020) Whole-exome sequencing identified two novel mutations of DYNC2LI1 in fetal skeletal ciliopathy. Mol Genet Genomic Med 8(12):e1524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Duran I, Taylor SP, Zhang W, Martin J, Forlenza KN, Spiro RP, Nickerson DA, Bamshad M, Cohn DH, Krakow D (2016) Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome. Sci Rep 6:34232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang W, Taylor SP, Nevarez L, Lachman RS, Nickerson DA, Bamshad M, University of Washington Center for Mendelian Genomics Consortium, Krakow D, Cohn DH (2016) IFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome. Hum Mol Genet 25(18):4012-4020

  36. Ishida Y, Tasaki K, Katoh Y, Nakayama K (2022) Molecular basis underlying the ciliary defects caused by IFT52 variations found in skeletal ciliopathies. Mol Biol Cell 33(9):ar83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. O’Connor MB, Gallagher DP, Mulloy E (2008) Jeune syndrome. Postgrad Med J 84(996):559

    Article  CAS  PubMed  Google Scholar 

  38. Schmidts M (2014) Clinical genetics and pathobiology of ciliary chondrodysplasias. J Pediatr Genet 3(2):46–94

    PubMed  Google Scholar 

  39. Handa A, Voss U, Hammarsjo A, Grigelioniene G, Nishimura G (2020) Skeletal ciliopathies: a pattern recognition approach. Jpn J Radiol 38(3):193–206

    Article  CAS  PubMed  Google Scholar 

  40. Stembalska A, Rydzanicz M, Klaniewska M, Dudarewicz L, Pollak A, Biela M, Stawinski P, Ploski R, Smigiel R (2022) Prenatal diagnosis of Jeune syndrome caused by compound heterozygous variants in DYNC2H1 gene-case report with rapid WES procedure and differential diagnosis of lethal skeletal dysplasias. Genes (Basel) 13(8):1339

    Article  CAS  PubMed  Google Scholar 

  41. Miller KA, Ah-Cann CJ, Welfare MF, Tan TY, Pope K, Caruana G, Freckmann ML, Savarirayan R, Bertram JF, Dobbie MS et al (2013) Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome. PLoS Genet 9(8):e1003746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang C, Yuan X, Yang S (2013) IFT80 is essential for chondrocyte differentiation by regulating Hedgehog and Wnt signaling pathways. Exp Cell Res 319(5):623–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Trobisch P, Suess O, Schwab F (2010) Idiopathic scoliosis. Dtsch Arztebl Int 107(49):875–883; quiz 884

  44. Altaf F, Gibson A, Dannawi Z, Noordeen H (2013) Adolescent idiopathic scoliosis. BMJ 346:f2508

    Article  PubMed  Google Scholar 

  45. Peng Y, Wang SR, Qiu GX, Zhang JG, Zhuang QY (2020) Research progress on the etiology and pathogenesis of adolescent idiopathic scoliosis. Chin Med J (Engl) 133(4):483–493

    Article  CAS  PubMed  Google Scholar 

  46. Oliazadeh N, Gorman KF, Eveleigh R, Bourque G, Moreau A (2017) identification of elongated primary cilia with impaired mechanotransduction in idiopathic scoliosis patients. Sci Rep 7:44260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Buchan JG, Gray RS, Gansner JM, Alvarado DM, Burgert L, Gitlin JD, Gurnett CA, Goldsmith MI (2014) Kinesin family member 6 (kif6) is necessary for spine development in zebrafish. Dev Dyn 243(12):1646–1657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Grimes DT, Boswell CW, Morante NF, Henkelman RM, Burdine RD, Ciruna B (2016) Zebrafish models of idiopathic scoliosis link cerebrospinal fluid flow defects to spine curvature. Science 352(6291):1341–1344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rose CD, Pompili D, Henke K, Van Gennip JLM, Meyer-Miner A, Rana R, Gobron S, Harris MP, Nitz M, Ciruna B (2020) SCO-spondin defects and neuroinflammation are conserved mechanisms driving spinal deformity across genetic models of idiopathic scoliosis. Curr Biol 30(12):2363-2373.e2366

    Article  CAS  PubMed  Google Scholar 

  50. Jiang H, Liang S, He K, Hu J, Xu E, Lin T, Meng Y, Zhao J, Ma J, Gao R et al (2020) Exome sequencing analysis identifies frequent oligogenic involvement and FLNB variants in adolescent idiopathic scoliosis. J Med Genet 57(6):405–413

    Article  PubMed  Google Scholar 

  51. Forsythe E, Beales PL (2013) Bardet–Biedl syndrome. Eur J Hum Genet 21(1):8–13

    Article  CAS  PubMed  Google Scholar 

  52. Tsang SH, Aycinena ARP, Sharma T (2018) Ciliopathy: Bardet–Biedl syndrome. Adv Exp Med Biol 1085:171–174

    Article  PubMed  Google Scholar 

  53. Parisi MA (2019) The molecular genetics of Joubert syndrome and related ciliopathies: the challenges of genetic and phenotypic heterogeneity. Transl Sci Rare Dis 4(1–2):25–49

    PubMed  PubMed Central  Google Scholar 

  54. Helm BM, Willer JR, Sadeghpour A, Golzio C, Crouch E, Vergano SS, Katsanis N, Davis EE (2017) Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer–Saldino syndrome. Hum Genomics 11(1):16

    Article  PubMed  PubMed Central  Google Scholar 

  55. Walczak-Sztulpa J, Eggenschwiler J, Osborn D, Brown DA, Emma F, Klingenberg C, Hennekam RC, Torre G, Garshasbi M, Tzschach A et al (2010) Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am J Hum Genet 86(6):949–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Shaheen R, Jiang N, Alzahrani F, Ewida N, Al-Sheddi T, Alobeid E, Musaev D, Stanley V, Hashem M, Ibrahim N et al (2019) Bi-allelic mutations in FAM149B1 cause abnormal primary cilium and a range of ciliopathy phenotypes in humans. Am J Hum Genet 104(4):731–737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bialas NJ, Inglis PN, Li C, Robinson JF, Parker JD, Healey MP, Davis EE, Inglis CD, Toivonen T, Cottell DC et al (2009) Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. J Cell Sci 122(Pt 5):611–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Green JS, Parfrey PS, Harnett JD, Farid NR, Cramer BC, Johnson G, Heath O, McManamon PJ, O’Leary E, Pryse-Phillips W (1989) The cardinal manifestations of Bardet–Biedl syndrome, a form of Laurence–Moon–Biedl syndrome. N Engl J Med 321(15):1002–1009

    Article  CAS  PubMed  Google Scholar 

  59. Kaushik AP, Martin JA, Zhang Q, Sheffield VC, Morcuende JA (2009) Cartilage abnormalities associated with defects of chondrocytic primary cilia in Bardet–Biedl syndrome mutant mice. J Orthop Res 27(8):1093–1099

    Article  PubMed  Google Scholar 

  60. Muller J, Stoetzel C, Vincent MC, Leitch CC, Laurier V, Danse JM, Helle S, Marion V, Bennouna-Greene V, Vicaire S et al (2010) Identification of 28 novel mutations in the Bardet–Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease. Hum Genet 127(5):583–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Brunetti-Pierri R, Karali M, Testa F, Cappuccio G, Onore ME, Romano F, De Rosa G, Tedeschi E, Brunetti-Pierri N, Banfi S et al (2021) Mild clinical presentation of Joubert syndrome in a male adult carrying biallelic MKS1 truncating variants. Diagnostics (Basel) 11(7):1218

    Article  PubMed  Google Scholar 

  62. Bujakowska KM, Zhang Q, Siemiatkowska AM, Liu Q, Place E, Falk MJ, Consugar M, Lancelot ME, Antonio A, Lonjou C et al (2015) Mutations in IFT172 cause isolated retinal degeneration and Bardet–Biedl syndrome. Hum Mol Genet 24(1):230–242

    Article  CAS  PubMed  Google Scholar 

  63. Kousi M, Soylemez O, Ozanturk A, Mourtzi N, Akle S, Jungreis I, Muller J, Cassa CA, Brand H, Mokry JA et al (2020) Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy. Nat Genet 52(11):1145–1150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Davis EE, Zhang Q, Liu Q, Diplas BH, Davey LM, Hartley J, Stoetzel C, Szymanska K, Ramaswami G, Logan CV et al (2011) TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 43(3):189–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Romani M, Micalizzi A, Valente EM (2013) Joubert syndrome: congenital cerebellar ataxia with the molar tooth. Lancet Neurol 12(9):894–905

    Article  PubMed  Google Scholar 

  66. De Mori R, Romani M, D’Arrigo S, Zaki MS, Lorefice E, Tardivo S, Biagini T, Stanley V, Musaev D, Fluss J et al (2017) Hypomorphic recessive variants in SUFU impair the sonic hedgehog pathway and cause Joubert syndrome with cranio-facial and skeletal defects. Am J Hum Genet 101(4):552–563

    Article  PubMed  PubMed Central  Google Scholar 

  67. Halbritter J, Bizet AA, Schmidts M, Porath JD, Braun DA, Gee HY, McInerney-Leo AM, Krug P, Filhol E, Davis EE et al (2013) Defects in the IFT-B component IFT172 cause Jeune and Mainzer–Saldino syndromes in humans. Am J Hum Genet 93(5):915–925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hammarsjo A, Wang Z, Vaz R, Taylan F, Sedghi M, Girisha KM, Chitayat D, Neethukrishna K, Shannon P, Godoy R et al (2017) Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies. Sci Rep 7(1):15585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Travaglini L, Brancati F, Silhavy J, Iannicelli M, Nickerson E, Elkhartoufi N, Scott E, Spencer E, Gabriel S, Thomas S et al (2013) Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders. Eur J Hum Genet 21(10):1074–1078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B et al (2010) Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 42(7):619–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Majewski F, Stoss H, Goecke T, Kemperdick H (1983) Are bowing of long tubular bones and preaxial polydactyly signs of the Meckel syndrome? Hum Genet 65(2):125–133

    Article  CAS  PubMed  Google Scholar 

  72. Castilla EE, Lugarinho R, da Graca DM, Salgado LJ (1998) Associated anomalies in individuals with polydactyly. Am J Med Genet 80(5):459–465

    Article  CAS  PubMed  Google Scholar 

  73. Romani M, Micalizzi A, Kraoua I, Dotti MT, Cavallin M, Sztriha L, Ruta R, Mancini F, Mazza T, Castellana S et al (2014) Mutations in B9D1 and MKS1 cause mild Joubert syndrome: expanding the genetic overlap with the lethal ciliopathy Meckel syndrome. Orphanet J Rare Dis 9:72

    Article  PubMed  PubMed Central  Google Scholar 

  74. Leightner AC, Hommerding CJ, Peng Y, Salisbury JL, Gainullin VG, Czarnecki PG, Sussman CR, Harris PC (2013) The Meckel syndrome protein meckelin (TMEM67) is a key regulator of cilia function but is not required for tissue planar polarity. Hum Mol Genet 22(10):2024–2040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mendley SR, Poznanski AK, Spargo BH, Langman CB (1995) Hereditary sclerosing glomerulopathy in the conorenal syndrome. Am J Kidney Dis 25(5):792–797

    Article  CAS  PubMed  Google Scholar 

  76. Perrault I, Saunier S, Hanein S, Filhol E, Bizet AA, Collins F, Salih MA, Gerber S, Delphin N, Bigot K et al (2012) Mainzer–Saldino syndrome is a ciliopathy caused by IFT140 mutations. Am J Hum Genet 90(5):864–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ryan R, Failler M, Reilly ML, Garfa-Traore M, Delous M, Filhol E, Reboul T, Bole-Feysot C, Nitschke P, Baudouin V et al (2018) Functional characterization of tektin-1 in motile cilia and evidence for TEKT1 as a new candidate gene for motile ciliopathies. Hum Mol Genet 27(2):266–282

    Article  CAS  PubMed  Google Scholar 

  78. Lin AE, Traum AZ, Sahai I, Keppler-Noreuil K, Kukolich MK, Adam MP, Westra SJ, Arts HH (2013) Sensenbrenner syndrome (Cranioectodermal dysplasia): clinical and molecular analyses of 39 patients including two new patients. Am J Med Genet A 161A(11):2762–2776

    Article  PubMed  Google Scholar 

  79. Takahara M, Katoh Y, Nakamura K, Hirano T, Sugawa M, Tsurumi Y, Nakayama K (2018) Ciliopathy-associated mutations of IFT122 impair ciliary protein trafficking but not ciliogenesis. Hum Mol Genet 27(3):516–528

    Article  CAS  PubMed  Google Scholar 

  80. Cordova-Fletes C, Becerra-Solano LE, Rangel-Sosa MM, Rivas-Estilla AM, Alberto Galan-Huerta K, Ortiz-Lopez R, Rojas-Martinez A, Juarez-Vazquez CI, Garcia-Ortiz JE (2018) Uncommon runs of homozygosity disclose homozygous missense mutations in two ciliopathy-related genes (SPAG17 and WDR35) in a patient with multiple brain and skeletal anomalies. Eur J Med Genet 61(3):161–167

    Article  PubMed  Google Scholar 

  81. Girisha KM, Shukla A, Trujillano D, Bhavani GS, Hebbar M, Kadavigere R, Rolfs A (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin Genet 90(6):536–539

    Article  CAS  PubMed  Google Scholar 

  82. Walczak-Sztulpa J, Wawrocka A, Doornbos C, van Beek R, Sowinska-Seidler A, Jamsheer A, Bukowska-Olech E, Latos-Bielenska A, Grenda R, Bongers E et al (2022) Identical IFT140 variants cause variable skeletal ciliopathy phenotypes—challenges for the accurate diagnosis. Front Genet 13:931822

    Article  PubMed  PubMed Central  Google Scholar 

  83. Ishida Y, Kobayashi T, Chiba S, Katoh Y, Nakayama K (2021) Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia. Hum Mol Genet 30(3–4):213–225

    Article  CAS  PubMed  Google Scholar 

  84. Kreiborg S, Barr M Jr, Cohen MM Jr (1992) Cervical spine in the Apert syndrome. Am J Med Genet 43(4):704–708

    Article  CAS  PubMed  Google Scholar 

  85. Glaser RL, Broman KW, Schulman RL, Eskenazi B, Wyrobek AJ, Jabs EW (2003) The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am J Hum Genet 73(4):939–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Koyama E, Young B, Nagayama M, Shibukawa Y, Enomoto-Iwamoto M, Iwamoto M, Maeda Y, Lanske B, Song B, Serra R et al (2007) Conditional Kif3a ablation causes abnormal hedgehog signaling topography, growth plate dysfunction, and excessive bone and cartilage formation during mouse skeletogenesis. Development 134(11):2159–2169

    Article  CAS  PubMed  Google Scholar 

  87. Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, Alfadhel M, Lewis RA, Eyaid W, Banin E et al (2008) Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet 40(4):443–448

    Article  CAS  PubMed  Google Scholar 

  88. Yuan X, Yang S (2015) Deletion of IFT80 impairs epiphyseal and articular cartilage formation due to disruption of chondrocyte differentiation. PLoS ONE 10(6):e0130618

    Article  PubMed  PubMed Central  Google Scholar 

  89. Barroso-Gil M, Olinger E, Ramsbottom SA, Molinari E, Miles CG, Sayer JA (2021) Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype–phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies. Mol Genet Genomic Med 9(12):e1603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Salonen R, Paavola P (1998) Meckel syndrome. J Med Genet 35(6):497–501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Williams CL, Masyukova SV, Yoder BK (2010) Normal ciliogenesis requires synergy between the cystic kidney disease genes MKS-3 and NPHP-4. J Am Soc Nephrol 21(5):782–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Barker AR, Thomas R, Dawe HR (2014) Meckel–Gruber syndrome and the role of primary cilia in kidney, skeleton, and central nervous system development. Organogenesis 10(1):96–107

    Article  PubMed  Google Scholar 

  93. Beals RK, Weleber RG (2007) Conorenal dysplasia: a syndrome of cone-shaped epiphysis, renal disease in childhood, retinitis pigmentosa and abnormality of the proximal femur. Am J Med Genet A 143A(20):2444–2447

    Article  PubMed  Google Scholar 

  94. Wallmeier J, Nielsen KG, Kuehni CE, Lucas JS, Leigh MW, Zariwala MA, Omran H (2020) Motile ciliopathies. Nat Rev Dis Primers 6(1):77

    Article  PubMed  Google Scholar 

  95. Young ID (1989) Cranioectodermal dysplasia (Sensenbrenner’s syndrome). J Med Genet 26(6):393–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Smith C, Lamont RE, Wade A, Bernier FP, Parboosingh JS, Innes AM (2016) A relatively mild skeletal ciliopathy phenotype consistent with cranioectodermal dysplasia is associated with a homozygous nonsynonymous mutation in WDR35. Am J Med Genet A 170(3):760–765

    Article  CAS  PubMed  Google Scholar 

  97. Pignolo RJ, Wang H, Kaplan FS (2019) Fibrodysplasia ossificans progressiva (FOP): a segmental progeroid syndrome. Front Endocrinol (Lausanne) 10:908

    Article  PubMed  Google Scholar 

  98. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38(5):525–527

    Article  CAS  PubMed  Google Scholar 

  99. Allen RS, Tajer B, Shore EM, Mullins MC (2020) Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. eLife. https://doi.org/10.7554/eLife.53761

    Article  PubMed  PubMed Central  Google Scholar 

  100. Álvarez-Satta M, Lago-Docampo M, Bea-Mascato B, Solarat C, Castro-Sánchez S, Christensen ST, Valverde D (2021) ALMS1 regulates TGF-β signaling and morphology of primary cilia. Front Cell Dev Biol 9:623829

    Article  PubMed  PubMed Central  Google Scholar 

  101. Mönnich M, Borgeskov L, Breslin L, Jakobsen L, Rogowski M, Doganli C, Schrøder JM, Mogensen JB, Blinkenkjær L, Harder LM et al (2018) CEP128 localizes to the subdistal appendages of the mother centriole and regulates TGF-β/BMP signaling at the primary cilium. Cell Rep 22(10):2584–2592

    Article  PubMed  Google Scholar 

  102. Wu M, Chen G, Li YP (2016) TGF-beta and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res 4:16009

    Article  PubMed  PubMed Central  Google Scholar 

  103. Xiao Z, Zhang S, Cao L, Qiu N, David V, Quarles LD (2010) Conditional disruption of Pkd1 in osteoblasts results in osteopenia due to direct impairment of bone formation. J Biol Chem 285(2):1177–1187

    Article  CAS  PubMed  Google Scholar 

  104. Noda K, Kitami M, Kitami K, Kaku M, Komatsu Y (2016) Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development. Proc Natl Acad Sci USA 113(19):E2589-2597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Xiang W, Jiang T, Hao X, Wang R, Yao X, Sun K, Guo F, Xu T (2019) Primary cilia and autophagy interaction is involved in mechanical stress mediated cartilage development via ERK/mTOR axis. Life Sci 218:308–313

    Article  CAS  PubMed  Google Scholar 

  106. Hruba E, Kavkova M, Dalecka L, Macholan M, Zikmund T, Varecha M, Bosakova M, Kaiser J, Krejci P, Hovorakova M et al (2021) Loss of sprouty produces a ciliopathic skeletal phenotype in mice through upregulation of hedgehog signaling. J Bone Miner Res 36(11):2258–2274

    Article  CAS  PubMed  Google Scholar 

  107. Walton KD, Gumucio DL (2021) Hedgehog signaling in intestinal development and homeostasis. Annu Rev Physiol 83:359–380

    Article  CAS  PubMed  Google Scholar 

  108. Bangs F, Anderson KV (2017) Primary cilia and mammalian hedgehog signaling. Cold Spring Harb Perspect Biol 9(5):a028175

    Article  PubMed  PubMed Central  Google Scholar 

  109. Briscoe J, Therond PP (2013) The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol 14(7):416–429

    Article  PubMed  Google Scholar 

  110. Haycraft CJ, Zhang Q, Song B, Jackson WS, Detloff PJ, Serra R, Yoder BK (2007) Intraflagellar transport is essential for endochondral bone formation. Development 134(2):307–316

    Article  CAS  PubMed  Google Scholar 

  111. Shao YY, Wang L, Welter JF, Ballock RT (2012) Primary cilia modulate Ihh signal transduction in response to hydrostatic loading of growth plate chondrocytes. Bone 50(1):79–84

    Article  CAS  PubMed  Google Scholar 

  112. Qiu N, Cao L, David V, Quarles LD, Xiao Z (2010) Kif3a deficiency reverses the skeletal abnormalities in Pkd1 deficient mice by restoring the balance between osteogenesis and adipogenesis. PLoS ONE 5(12):e15240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bimonte S, De Angelis A, Quagliata L, Giusti F, Tammaro R, Dallai R, Ascenzi MG, Diez-Roux G, Franco B (2011) Ofd1 is required in limb bud patterning and endochondral bone development. Dev Biol 349(2):179–191

    Article  CAS  PubMed  Google Scholar 

  114. Mill P, Lockhart PJ, Fitzpatrick E, Mountford HS, Hall EA, Reijns MA, Keighren M, Bahlo M, Bromhead CJ, Budd P et al (2011) Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis. Am J Hum Genet 88(4):508–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chang CF, Ramaswamy G, Serra R (2012) Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis. Osteoarthr Cartil 20(2):152–161

    Article  Google Scholar 

  116. Stiff T, Alagoz M, Alcantara D, Outwin E, Brunner HG, Bongers EM, O’Driscoll M, Jeggo PA (2013) Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of Meier–Gorlin syndrome. PLoS Genet 9(3):e1003360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Moon H, Song J, Shin JO, Lee H, Kim HK, Eggenschwiller JT, Bok J, Ko HW (2014) Intestinal cell kinase, a protein associated with endocrine-cerebro-osteodysplasia syndrome, is a key regulator of cilia length and Hedgehog signaling. Proc Natl Acad Sci USA 111(23):8541–8546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chang CF, Serra R (2013) Ift88 regulates Hedgehog signaling, Sfrp5 expression, and beta-catenin activity in post-natal growth plate. J Orthop Res 31(3):350–356

    Article  CAS  PubMed  Google Scholar 

  119. Kyun ML, Kim SO, Lee HG, Hwang JA, Hwang J, Soung NK, Cha-Molstad H, Lee S, Kwon YT, Kim BY et al (2020) Wnt3a stimulation promotes primary ciliogenesis through beta-catenin phosphorylation-induced reorganization of centriolar satellites. Cell Rep 30(5):1447-1462.e1445

    Article  CAS  PubMed  Google Scholar 

  120. Lee KH, Johmura Y, Yu LR, Park JE, Gao Y, Bang JK, Zhou M, Veenstra TD, Yeon Kim B, Lee KS (2012) Identification of a novel Wnt5a-CK1varepsilon-Dvl2-Plk1-mediated primary cilia disassembly pathway. EMBO J 31(14):3104–3117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kaku M, Komatsu Y (2017) Functional diversity of ciliary proteins in bone development and disease. Curr Osteoporos Rep 15(2):96–102

    Article  PubMed  Google Scholar 

  122. Lowery JW, Rosen V (2018) The BMP pathway and its inhibitors in the skeleton. Physiol Rev 98(4):2431–2452

    Article  CAS  PubMed  Google Scholar 

  123. Guo X, Wang XF (2009) Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res 19(1):71–88

    Article  CAS  PubMed  Google Scholar 

  124. Anvarian Z, Mykytyn K, Mukhopadhyay S, Pedersen LB, Christensen ST (2019) Cellular signalling by primary cilia in development, organ function and disease. Nat Rev Nephrol 15(4):199–219

    Article  PubMed  PubMed Central  Google Scholar 

  125. Clement CA, Ajbro KD, Koefoed K, Vestergaard ML, Veland IR, Henriques de Jesus MP, Pedersen LB, Benmerah A, Andersen CY, Larsen LA et al (2013) TGF-beta signaling is associated with endocytosis at the pocket region of the primary cilium. Cell Rep 3(6):1806–1814

    Article  CAS  PubMed  Google Scholar 

  126. Chen G, Deng C, Li YP (2012) TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci 8(2):272–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ehnert S, Sreekumar V, Aspera-Werz RH, Sajadian SO, Wintermeyer E, Sandmann GH, Bahrs C, Hengstler JG, Godoy P, Nussler AK (2017) TGF-beta1 impairs mechanosensation of human osteoblasts via HDAC6-mediated shortening and distortion of primary cilia. J Mol Med (Berl) 95(6):653–663

    Article  CAS  PubMed  Google Scholar 

  128. Zhang C, Zhang S, Sun Y (2019) Expression of IFT140 during bone development. J Histochem Cytochem 67(10):723–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Wang T, Yang L, Jiang J, Liu Y, Fan Z, Zhong C, He C (2019) Pulsed electromagnetic fields: promising treatment for osteoporosis. Osteoporos Int 30(2):267–276

    Article  CAS  PubMed  Google Scholar 

  130. Yan JL, Zhou J, Ma HP, Ma XN, Gao YH, Shi WG, Fang QQ, Ren Q, Xian CJ, Chen KM (2015) Pulsed electromagnetic fields promote osteoblast mineralization and maturation needing the existence of primary cilia. Mol Cell Endocrinol 404:132–140

    Article  CAS  PubMed  Google Scholar 

  131. Zhou J, Gao YH, Zhu BY, Shao JL, Ma HP, Xian CJ, Chen KM (2019) Sinusoidal electromagnetic fields increase peak bone mass in rats by activating Wnt10b/beta-catenin in primary cilia of osteoblasts. J Bone Miner Res 34(7):1336–1351

    Article  CAS  PubMed  Google Scholar 

  132. Jiang Y, Tuan RS (2015) Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat Rev Rheumatol 11(4):206–212

    Article  PubMed  Google Scholar 

  133. Yang C, Zhang R, Lin H, Wang H (2019) Insights into the molecular regulatory network of pathomechanisms in osteochondroma. J Cell Biochem 120(10):16362–16369

    Article  CAS  PubMed  Google Scholar 

  134. de Andrea CE, Wiweger M, Prins F, Bovee JV, Romeo S, Hogendoorn PC (2010) Primary cilia organization reflects polarity in the growth plate and implies loss of polarity and mosaicism in osteochondroma. Lab Investig 90(7):1091–1101

    Article  PubMed  Google Scholar 

  135. de Andrea CE, Zhu JF, Jin H, Bovee JV, Jones KB (2015) Cell cycle deregulation and mosaic loss of Ext1 drive peripheral chondrosarcomagenesis in the mouse and reveal an intrinsic cilia deficiency. J Pathol 236(2):210–218

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank AJE (https://www.aje.cn/) for their assistance with English language editing.

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  1. Bowen Lai and Heng Jiang have contributed equally to this work.

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  1. Department of Orthopedics, Changzheng Hospital, Second Military Medical University, Fengyang Road 415, Shanghai, 200003, China

    Bowen Lai, Heng Jiang, Yuan Gao & Xuhui Zhou

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BL, conceptualization; BL and HJ, data curation; BL and YG, methodology; YG, project administration; XZ, resources; YG, software; XZ, supervision; HJ and XZ, visualization; BL and HJ, roles/writing—original draft; YG and XZ, writing—review and editing.

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Correspondence to Xuhui Zhou.

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Lai, B., Jiang, H., Gao, Y. et al. Skeletal ciliopathy: pathogenesis and related signaling pathways. Mol Cell Biochem 479, 811–823 (2024). https://doi.org/10.1007/s11010-023-04765-5

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