Cilia and Human Disease


Cilia and centrioles are highly conserved organelles that have hundreds of proteins associated with them. Studies in mice have shown that these organelles are essential for mammalian development and mice that cannot assemble them die in utero. However, mutations in many cilia and centriole genes cause human diseases that show a great range in defects. Defects in centrioles are associated with microcephaly and mental retardation. The reduction in brain size is related to the loss of neuronal progenitor cells. Defects in centrioles may also be associated with Sjögren syndrome, an autoimmune disease, because of defects in formation of the immunological synapse. Defects that cause immotile cilia result in chronic respiratory infections, infertility, and congenital heart defects. Defects in primary cilia share various symptoms that include loss of vision, obesity, diabetes, cystic kidney disease, mental retardation, polydactyly, and short bones. Many of these diseases are associated with the transport and sorting of receptors onto the ciliary membrane for sensing the environment.

Key Concepts:

  • Cilia perform functions in many different tissues and during development.

  • Many ciliary mutations affect multiple tissues and organs.

  • Key signalling pathways require cilia.

  • Orientation of the spindle during mitosis requires functional centrioles.

Keywords: cilia; centriole; basal body; transition zone; microcephaly; autoimmune disease; cystic kidney disease; obesity; retinal degeneration; polydactyly

Figure 1.

Structure of the cilium. The cilium is a hair‐like protrusion covered by membrane with a unique content from the rest of the plasma membrane. The basal bodies, which interconvert to centrioles during mitosis, are composed of triplet microtubules that serve as a template for the axoneme. The axoneme has doublet microtubules, with motile cilia also having a central pair of microtubules not found in primary cilia. The dynein arms and radial spokes are required for the motility of cilia. The nexin links connect the doublet microtubules to each other and prevent the microtubules from sliding past each other. Vesicles destined for the cilium are sorted in the Golgi complex and the BBsome is thought to help proteins and vesicles enter the cilium. The transition fibres are attachments between the basal body and the plasma membrane and act as a sieve to prevent passive diffusion of proteins between the cytoplasm and the cilium. Cargo is transported to the tip of the cilium via anterograde transport by IFT complex B. Cargo returns to the cytoplasm by retrograde transport of IFT complex A. The diseases and syndromes described in the article have defects in the basal body, cilium, or the proteins needed to make these structures.

Figure 2.

Ciliopathies have a broad spectrum of symptoms. The photoreceptor is a specialised cilium and many of the ciliopathies have vision or other eye defects. The severity of eye problems is indicated by colour with the most severe in dark purple and least severe in light purple. Both the kidneys and liver are commonly affected. Bone defects manifest as either shortened long bones or polydactyly. Defects in motile cilia can lead to increased incidence of respiratory tract infections. Laterality defects (situs inversus) where the organs placement has switched sides, is the result of motile cilia of the embryonic node not beating properly. Defects in cilia found in the brain can result in mental retardation or brain malformations. Obesity is also associated with ciliopathies, although the connection between obesity and cilia is not clear. Many of the ciliopathies share symptoms and many of the implicated genes are mutated in multiple disorders. Adapted from Mockel et al. with permission from Elsevier.

Figure 3.

Spindle position controls neural differentiation and development of microcephaly. Neuroepithelial progenitors in normal brains divide both symmetrically (top) and asymmetrically (bottom). The result is an increase in the progenitor pool and production of differentiating cells. In microcephaly, there is a loss of symmetric cell division and a corresponding loss of neuroepithelial progenitors leading to small brains (Konno et al., ).



Arts HH, Bongers EM, Mans DA et al. (2011) C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome. Journal of Medical Genetics 48(6): 390–395.

Azimzadeh J and Bornens M (2007) Structure and duplication of the centrosome. Journal of Cell Science 120(Pt 13): 2139–2142.

Baala L, Romano S, Khaddour R et al. (2007) The Meckel‐Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. American Journal of Human Genetics 80(1): 186–194.

Beales PL, Bland E, Tobin JL et al. (2007) IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nature Genetics 39(6): 727–729.

Behal RH, Miller MS, Qin H et al. (2011) Subunit Interactions and Organization of the Chlamydomonas reinhardtii Intraflagellar Transport Complex A. Journal of Biological Chemistry. 287(15): 11689–11703.

Bergmann C, Senderek J, Sedlacek B et al. (2003) Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1). Journal of the American Society of Nephrology 14(1): 76–89.

Bredrup C, Saunier S, Oud MM et al. (2011) Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT‐A gene WDR19. American Journal of Human Genetics 89(5): 634–643.

Brito DA, Gouveia SM and Bettencourt‐Dias M (2012) Deconstructing the centriole: structure and number control. Current Opinion in Cell Biology 24(1): 4–13.

Collin GB, Marshall JD, Ikeda A et al. (2002) Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nature Genetics 31(1): 74–78.

Craige B, Tsao CC, Diener DR et al. (2010) CEP290 tethers flagellar transition zone microtubules to the membrane and regulates flagellar protein content. Journal of Cell Biology 190(5): 927–940.

Czarnecki PG and Shah JV (2012) The ciliary transition zone: from morphology and molecules to medicine. Trends in Cell Biology. 22(5): 201–210.

Dagoneau N, Goulet M, Genevieve D et al. (2009) DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib‐polydactyly syndrome, type III. American Journal of Human Genetics 84(5): 706–711.

Deane JA, Cole DG, Seeley ES, Diener DR and Rosenbaum JL (2001) Localization of intraflagellar transport protein IFT52 identifies basal body transitional fibers as the docking site for IFT particles. Current Biology 11(20): 1586–1590.

Dutcher SK (2003) Elucidation of basal body and centriole functions in Chlamydomonas reinhardtii. Traffic 4(7): 443–451.

Dutcher SK, Li L, Lin H et al. (2012) Whole‐genome sequencing to identify mutants and polymorphisms in Chlamydomonas reinhardtii. G3 (Bethesda) 2(1): 15–22.

Esteban MA, Harten SK, Tran MG and Maxwell PH (2006) Formation of primary cilia in the renal epithelium is regulated by the von Hippel‐Lindau tumor suppressor protein. Journal of the American Society of Nephrology 17(7): 1801–1806.

Garcia‐Gonzalo FR, Corbit KC, Sirerol‐Piquer MS et al. (2011) A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nature Genetics 43(8): 776–784.

Gilissen C, Arts HH, Hoischen A et al. (2010) Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. American Journal of Human Genetics 87(3): 418–423.

Gonczy P, Grill S, Stelzer EH, Kirkham M and Hyman AA (2001) Spindle positioning during the asymmetric first cell division of Caenorhabditis elegans embryos. Novartis Foundation Symposium 237: 164–175, discussion 176‐81.

Higgins J, Midgley C, Bergh AM et al. (2010) Human ASPM participates in spindle organisation, spindle orientation and cytokinesis. BMC Cell Biology 11: 85.

den Hollander AI, Roepman R, Koenekoop RK and Cremers FP (2008) Leber congenital amaurosis: genes, proteins and disease mechanisms. Progress in Retinal and Eye Research 27(4): 391–419.

Hudak LM, Lunt S, Chang CH and Winkler E (2010) The intraflagellar transport protein ift80 is essential for photoreceptor survival in a zebrafish model of jeune asphyxiating thoracic dystrophy. Investigative Ophthalmology & Visual Science 51(7): 3792–3799.

Ice JA, Li H, Adrianto I et al. (2012) Genetics of Sjogren's syndrome in the genome‐wide association era. Journal of Autoimmunity.

Igarashi P and Somlo S (2007) Polycystic kidney disease. Journal of the American Society of Nephrology 18(5): 1371–1373.

Ishikawa H and Marshall WF (2011) Ciliogenesis: building the cell's antenna. Nature Reviews Molecular Cell Biology 12(4): 222–234.

Jin H, White SR, Shida T et al. (2010) The conserved Bardet‐Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell 141(7): 1208–1219.

Joy T, Cao H, Black G et al. (2007) Alstrom syndrome (OMIM 203800): a case report and literature review. Orphanet Journal of Rare Diseases 2: 49.

Kitagawa D, Vakonakis I, Olieric N et al. (2011a) Structural basis of the 9‐fold symmetry of centrioles. Cell 144(3): 364–375.

Kitagawa D, Kohlmaier G, Keller D et al. (2011b) Spindle positioning in human cells relies on proper centriole formation and on the microcephaly proteins CPAP and STIL. Journal of Cell Science 124(Pt 22): 3884–3893.

Konno D, Shioi G, Shitamukai A et al. (2008) Neuroepithelial progenitors undergo LGN‐dependent planar divisions to maintain self‐renewability during mammalian neurogenesis. Nature Cell Biology 10(1): 93–101.

Lai CK, Gupta N, Wen X et al. (2011) Functional characterization of putative cilia genes by high‐content analysis. Molecular Biology of the Cell 22(7): 1104–1119.

Li G, Vega R, Nelms K et al. (2007) A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genetics 3(1): e8.

Loktev AV, Zhang Q, Beck JS et al. (2008) A BBSome subunit links ciliogenesis, microtubule stability, and acetylation. Developmental Cell 15(6): 854–865.

Lutz MS and Burk RD (2006) Primary cilium formation requires von hippel‐lindau gene function in renal‐derived cells. Cancer Research 66(14): 6903–6907.

Merrill AE, Merriman B, Farrington‐Rock C et al. (2009) Ciliary abnormalities due to defects in the retrograde transport protein DYNC2H1 in short‐rib polydactyly syndrome. American Journal of Human Genetics 84(4): 542–549.

Mill P, Lockhart PJ, Fitzpatrick E et al. (2011) Human and mouse mutations in WDR35 cause short‐rib polydactyly syndromes due to abnormal ciliogenesis. American Journal of Human Genetics 88(4): 508–515.

Mockel A, Perdomo Y, Stutzmann F et al. (2011) Retinal dystrophy in Bardet‐Biedl syndrome and related syndromic ciliopathies. Progress in Retinal and Eye Research 30(4): 258–274.

Nachury MV, Loktev AV, Zhang Q et al. (2007) A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129(6): 1201–1213.

Parisi MA, Bennett CL, Eckert ML et al. (2004) The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. American Journal of Human Genetics 75(1): 82–91.

Rix S, Calmont A, Scrambler PJ and Beales PL (2011) An Ift80 mouse model of short rib polydactyly syndromes shows defects in hedgehog signalling without loss or malformation of cilia. Human Molecular Genetics 20(7): 1306–1314.

Rosales JL, Rattner JB and Lee KY (2010) The primary microcephaly 3 (MCPH3) interacting protein, p35 and its catalytic subunit, Cdk5, are centrosomal proteins. Cell Cycle 9(3): 618–620.

Sang L, Miller J, Corbit KC et al. (2011) Mapping the NPHP‐JBTS‐MKS protein network reveals ciliopathy disease genes and pathways. Cell 145(4): 513–528.

Schermer B, Genoiu C, Bartram M et al. (2006) The von Hippel‐Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. Journal of Cell Biology 175(4): 547–554.

Seo S, Baye LM, Schulz NP et al. (2010) BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proceedings of the National Academy of Sciences of the USA 107(4): 1488–1493.

Thiel C, Kessler K, Giessl A et al. (2011) NEK1 mutations cause short‐rib polydactyly syndrome type majewski. American Journal of Human Genetics 88(1): 106–114.

Thornton GK and Woods CG (2009) Primary microcephaly: do all roads lead to Rome? Trends in Genetics 25(11): 501–510.

Walczak‐Sztulpa J, Eggenscheiler J, Osborn D et al. (2010) Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. American Journal of Human Genetics 86(6): 949–956.

You Y, Huang T, Richer EJ et al. (2004) Role of f‐box factor foxj1 in differentiation of ciliated airway epithelial cells. American Journal of Physiology ‐ Lung Cellular and Molecular Physiology 286(4): L650–L657.

Zariwala MA, Omran H and Ferkol TW (2011) The emerging genetics of primary ciliary dyskinesia. Proceedings of the American Thoracic Society 8(5): 430–433.

Zhao C and Malicki J (2011) Nephrocystins and MKS proteins interact with IFT particle and facilitate transport of selected ciliary cargos. EMBO Journal 30(13): 2532–2544.

Further Reading

Andersen JS, Wilkinson CJ, Mayor T et al. (2003) Proteomic characterization of the human centrosome by protein correlation profiling. Nature 426: 570–574.

Girard D and Petrovsky N (2011) Alstrom syndrome: insights into the pathogenesis of metabolic disorders. Nature Reviews Endocrinology 7: 77–88.

Jakobsen L, Vanselow K, Skogs M et al. (2011) Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods. EMBO Journal 30: 1520–1535.

Keller LC, Romijn EP, Zamora I, Yates JR 3rd and Marshall WF (2005) Proteomic analysis of isolated Chlamydomonas centrioles reveals orthologs of ciliary‐disease genes. Current Biology 15: 1090–1098.

Kilburn CL, Pearson CG, Romijn EP et al. (2007) New Tetrahymena basal body protein components identify basal body domain structure. Journal of Cell Biology 178: 905–912.

Li JB, Gerdes JM, Haycraft CJ et al. (2004) Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117: 541–552.

Oh EC and Katsanis N (2012) Cilia in vertebrate development and disease. Development 139: 443–448.

Ostrowski LE, Blackburn K, Radde KM et al. (2002) A proteomic analysis of human cilia: identification of novel components. Molecular & Cellular Proteomics 1: 451–465.

Pazour GJ, Agrin N, Leszyk J and Witman GB (2005) Proteomic analysis of a eukaryotic cilium. Journal of Cell Biology 170: 103–113.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Albee, Alison J, and Dutcher, Susan K(Jul 2012) Cilia and Human Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022544]