Molecular Genetics of Joubert Syndrome


Joubert syndrome (JS) is an autosomal recessive or X‐linked congenital cerebellar ataxia characterised by a peculiar hindbrain–midbrain malformation, the ‘molar tooth sign’ (MTS). JS is characterised by neonatal hypotonia which later evolves into ataxia, developmental delay, abnormal eye movements, breathing abnormalities and intellectual disability. This neurological presentation can be variably complicated by the involvement of multiple organs such as the kidneys, retina, liver and skeleton.

JS is genetically heterogeneous, with 26 causative genes identified to date. All genes encode for proteins of the primary cilium, a nearly ubiquitous subcellular organelle that plays essential roles in embryonic development and cell functioning. Indeed, JS is part of ciliopathies, an expanding group of disorders that share many clinical and genetic determinants. The marked clinical and genetic heterogeneity of JS and ciliopathies may be explained by oligogenic inheritance and the existence of genetic modifiers.

Key Concepts:

  • Joubert syndrome (JS) is a congenital ataxia with autosomal or X‐linked recessive inheritance.

  • The diagnostic hallmark of JS is a peculiar cerebellar and brainstem malformation, the so‐called ‘molar tooth sign’ recognisable on brain imaging.

  • Neurological features of JS include hypotonia, ataxia, developmental delay, intellectual impairment, oculomotor abnormalities and alterations of the breathing pattern in neonatal age.

  • JS may present with variable involvement of the eyes, kidneys, liver, polydactyly and oral‐facial defects.

  • JS is genetically heterogeneous, with 26 genes identified to date, that are overall responsible of about half cases.

  • JS pathogenesis is related to the dysfunction of the primary cilium, making JS part of the expanding group of ‘ciliopathies’.

  • The primary cilium is an immotile organelle, located of the surface of nearly every cell type, that plays key roles in cellular functioning and embryonic development.

  • Ciliopathies are characterised by wide clinical and genetic heterogeneity, and present significant clinical and genetic overlap among distinct conditions.

  • Such complexity has been partly explained by showing oligogenic inheritance and the existence of genetic modifiers of the phenotype.

Keywords: Joubert syndrome; Meckel syndrome; primary cilium; cerebellum; cerebellar hypoplasia; ciliopathies; cerebellar ataxia; molar tooth sign; oligogenic inheritance

Figure 1.

T1‐weighted brain magnetic resonance imaging of a patient with Joubert syndrome showing the typical ‘molar tooth sign’ (MTS). (a) Axial section at the pontomesencephalic junction showing a deepened interpeduncolar fossa (thick arrow), elongated and thickened superior cerebellar peduncles (thin arrows) and umbrella shaped fourth ventricle (arrowhead). (b) Parasagittal section showing thickened, elongated and horizontalized superior cerebellar peduncle (arrow) and cerebellar vermian hypodysplasia (arrowhead).

Figure 2.

Schematic representation of a primary cilium, that is anchored to the cell through the basal body. The transition zone, where most of JS‐related proteins cluster in the ‘Tectonic’ complex, represents a functional gate to regulate the flux of proteins in and out of the cilium, so that to maintain it as a highly compartmentalized structure. Proteins entering the primary cilium are then trafficked up and down the ciliary length by means of anterograde and retrograde intraflagellary transport (red and green arrows, respectively), that is mediated by specific proteins complexes. Two major developmental pathways (Shh and Wnt) require a functional cilium for their correct functioning.



Adams NA, Awadein A and Toma HS (2007) The retinal ciliopathies. Ophthalmic Genetics 28(3): 113–125.

Aguilar A, Meunier A, Strehl L et al. (2012) Analysis of human samples reveals impaired SHH‐dependent cerebellar development in Joubert syndrome/Meckel syndrome. Proceedings of the National Academy of Sciences USA 109(42): 16951–16956.

Akizu N, Silhavy JL, Rosti RO et al. (2014) Mutations in CSPP1 lead to classical Joubert syndrome. American Journal of Human Genetics 94(1): 80–86.

Arts HH and Knoers NV (2012) Current insights into renal ciliopathies: what can genetics teach us? Pediatric Nephrology 28(6): 863–874.

Bell PD, Fitzgibbon W, Sas K et al. (2011) Loss of primary cilia upregulates renal hypertrophic signaling and promotes cystogenesis. Journal of the American Society of Nephrology 22(5): 839–848.

Brancati F, Barrano G, Silhavy JL et al. (2007) CEP290 mutations are frequently identified in the oculo‐renal form of Joubert syndrome‐related disorders. American Journal of Human Genetics 81(1): 104–113.

Brancati F, Dallapiccola B and Valente EM (2010) Joubert syndrome and related disorders. Orphanet Journal of Rare Disease 5: 20.

Brancati F, Travaglini L, Zablocka D et al. (2008) RPGRIP1L mutations are mainly associated with the cerebello‐renal phenotype of Joubert syndrome‐related disorders. Clinical Genetics 74(2): 164–170.

Cantagrel V, Silhavy JL, Bielas SL et al. (2008) Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. American Journal of Human Genetics 83(2): 170–179.

Castori M, Valente EM, Donati MA et al. (2005) NPHP1 gene deletion is a rare cause of Joubert syndrome related disorders. Journal of Medical Genetics 42(2): e9.

Chih B, Liu P, Chinn Y et al. (2012) A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nature Cell Biology 14(1): 61–72.

Clotman F, Libbrecht L, Killingsworth MC et al. (2008) Lack of cilia and differentiation defects in the liver of human foetuses with the Meckel syndrome. Liver International: Official Journal of the International Association for the Study of the Liver 28(3): 377–384.

Delous M, Baala L, Salomon R et al. (2007) The ciliary gene RPGRIP1L is mutated in cerebello‐oculo‐renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nature Genetics 39(7): 875–881.

Fattahi Z, Rostami P, Najmabadi A et al. (2014) Mutation profile of BBS genes in Iranian patients with Bardet‐Biedl syndrome: genetic characterization and report of nine novel mutations in five BBS genes. Journal of Human Genetics 59(7): 368–375.

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

Gerdes JM, Davis EE and Katsanis N (2009) The vertebrate primary cilium in development, homeostasis, and disease. Cell 137(1): 32–45.

Giouleme O, Nikolaidis N, Tziomalos K et al. (2006) Ductal plate malformation and congenital hepatic fibrosis clinical and histological findings in four patients. Hepatology Research: The Official Journal of the Japan Society of Hepatology 35(2): 147–150.

Gleeson JG, Keeler LC, Parisi MA et al. (2004) Molar tooth sign of the midbrain‐hindbrain junction: occurrence in multiple distinct syndromes. American Journal of Medical Genetics Part A 125A(2): 125–134; discussion 117.

Hagan N and Zervas M (2012) Wnt1 expression temporally allocates upper rhombic lip progenitors and defines their terminal cell fate in the cerebellum. Molecular and Cellular Neurosciences 49(2): 217–229.

Huang L, Szymanska K, Jensen VL et al. (2011) TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. American Journal of Human Genetics 89(6): 713–730.

Iannicelli M, Brancati F, Mougou‐Zerelli S et al. (2010) Novel TMEM67 mutations and genotype‐phenotype correlates in meckelin‐related ciliopathies. Human Mutation 31(5): E1319–E1331.

Jacoby M, Cox JJ, Gayral S et al. (2009) INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nature Genetetics 41(9): 1027–1031.

Joubert M, Eisenring JJ, Robb JP and Andermann F (1969) Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 19(9): 813–825.

Juric‐Sekhar G, Adkins J, Doherty D and Hevner RF (2012) Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia. Acta Neuropathologica 123(5): 695–709.

Khanna H, Davis EE, Murga‐Zamalloa CA et al. (2009) A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nature Genetetics 41(6): 739–745.

Lancaster MA, Gopal DJ, Kim J et al. (2011) Defective Wnt‐dependent cerebellar midline fusion in a mouse model of Joubert syndrome. Nature Medicine 17(6): 726–731.

Lewis PM, Gritli‐Linde A, Smeyne R, Kottmann A and McMahon AP (2004) Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Developmental Biology 270(2): 393–410.

Liem KF Jr, He M, Ocbina PJ and Anderson KV (2009) Mouse Kif7/Costal2 is a cilia‐associated protein that regulates Sonic hedgehog signaling. Proceedings of the National Academy of Sciences USA 106(32): 13377–13382.

Lopez E, Thauvin‐Robinet C, Reversade B et al. (2013) C5orf42 is the major gene responsible for OFD syndrome type VI. Human Genetics 133 (3): 367–377.

Louie CM, Caridi G, Lopes VS et al. (2010) AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nature Genetics 42(2): 175–180.

Maria BL, Hoang KB, Tusa RJ et al. (1997) “Joubert syndrome” revisited: key ocular motor signs with magnetic resonance imaging correlation. Journal of Child Neurology 12(7): 423–430.

Mougou‐Zerelli S, Thomas S, Szenker E et al. (2009) CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype‐phenotype correlation. Human Mutation 30(11): 1574–1582.

Novarino G, Akizu N and Gleeson JG (2011) Modeling human disease in humans: the ciliopathies. Cell 147(1): 70–79.

Pei Y, Brun SN, Markant SL et al. (2012) WNT signaling increases proliferation and impairs differentiation of stem cells in the developing cerebellum. Development 139(10): 1724–1733.

Poretti A, Dietrich Alber F, Brancati F et al. (2009) Normal cognitive functions in joubert syndrome. Neuropediatrics 40(6): 287–290.

Poretti A, Huisman TA, Scheer I and Boltshauser E (2011) Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AJNR American Journal of Neuroradiology 32(8): 1459–1463.

Poretti A, Vitiello G, Hennekam RC et al. (2012) Delineation and diagnostic criteria of oral‐facial‐digital syndrome type VI. Orphanet Journal of Rare Disease 7: 4.

Pugash D, Oh T, Godwin K et al. (2011) Sonographic ‘molar tooth’ sign in the diagnosis of Joubert syndrome. Ultrasound in Obstetrics & Gynecology: The Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology 38(5): 598–602.

Romani M, Micalizzi A, Kraoua I et al. (2014) Mutations in B9D1 and MKS1 cause mild Joubert syndrome: Expanding the genetic overlap with the lethal ciliopathy Meckel syndrome. Orphanet Journal of Rare Disease 9: 72.

Saleem SN and Zaki MS (2010) Role of MR imaging in prenatal diagnosis of pregnancies at risk for Joubert syndrome and related cerebellar disorders. AJNR American Journal of Neuroradiology 31(3): 424–429.

Salonen R (1984) The Meckel syndrome: clinicopathological findings in 67 patients. American Journal of Medical Genetics 18(4): 671–689.

Spassky N, Han YG, Aguilar A et al. (2008) Primary cilia are required for cerebellar development and Shh‐dependent expansion of progenitor pool. Developmental Biology 317(1): 246–259.

Srour M, Schwartzentruber J, Hamdan FF et al. (2012) Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. American Journal of Human Genetics 90(4): 693–700.

Tallila J, Salonen R, Kohlschmidt N, Peltonen L and Kestilä M (2009) Mutation spectrum of Meckel syndrome genes: one group of syndromes or several distinct groups? Human Mutation 30(8): E813–E830.

Tory K, Lacoste T, Burglen L et al. (2007) High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. Journal of the American Society of Nephrology 18(5): 1566–1575.

Travaglini L, Brancati F, Silhavy J et al. (2013) Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders. European Journal of Human Genetics 21: 1074–1078.

Valente EM, Brancati F, Silhavy JL et al. (2006) AHI1 gene mutations cause specific forms of Joubert syndrome‐related disorders. Annals of Neurology 59(3): 527–534.

Valente EM, Logan CV, Mougou‐Zerelli S et al. (2010) Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nature Genetics 42(7): 619–625.

Yachnis AT and Rorke LB (1999) Neuropathology of Joubert syndrome. Journal of Child Neurology 14(10): 655–659; discussion 669–672.

Zaghloul NA and Katsanis N (2010) Functional modules, mutational load and human genetic disease. Trends in Genetics 26(4): 168–176.

Further Reading

Badano JL, Leitch CC, Ansley SJ et al. (2006) Dissection of epistasis in oligogenic Bardet‐Biedl syndrome. Nature 439(7074): 326–330.

Barker AR, Thomas R and 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.

Fry AM, Leaper MJ and Bayliss R (2014) The primary cilium: guardian of organ development and homeostasis. Organogenesis 10(1): 62–68.

Guemez‐Gamboa A, Coufal NG and Gleeson JG (2014) Primary cilia in the developing and mature brain. Neuron 82(3): 511–521.

Hildebrandt F, Benzing T and Katsanis N (2011) Ciliopathies. New England Journal of Medicine 364(16): 1533–1543.

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

Valente EM, Rosti RO, Gibbs E and Gleeson JG (2014) Primary cilia in neurodevelopmental disorders. Nature Reviews Neurology 10(1): 27–36.

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

* Required Field

How to Cite close
Mancini, Francesca, Romani, Marta, Micalizzi, Alessia, and Valente, Enza Maria(Oct 2014) Molecular Genetics of Joubert Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024288]