Joubert syndrome: insights into brain development, cilium biology, and complex disease.

Joubert syndrome (JS) is a primarily autosomal recessive condition characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation (the "molar tooth sign"). Variable features include retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly. Recently, substantial progress has been made in our understanding of the genetic basis of JS, including identification of seven causal genes (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67/MKS3, ARL13B and CC2D2A). Despite this progress, the known genes account for <50% of cases and few strong genotype-phenotype correlations exist in JS; however, genetic testing can be prioritized based on clinical features. While all seven JS genes have been implicated in the function of the primary cilium/basal body organelle (PC/BB), little is known about how the PC/BB is required for brain, kidney, retina and liver development/function, nor how disruption of PC/BB function leads to diseases of these organs. Recent work on the function of the PC/BB indicates that the organelle is required for multiple signaling pathways including sonic hedgehog, WNT and platelet derived growth factor. Due to shared clinical features and underlying molecular pathophysiology, JS is included in the rapidly expanding group of disorders called ciliopathies. The ciliopathies are emerging as models for more complex diseases, where sequence variants in multiple genes contribute to the phenotype expressed in any given patient.

[1]  R. Dildrop,et al.  Ftm is a novel basal body protein of cilia involved in Shh signalling , 2007, Development.

[2]  Susumu Mori,et al.  Diffusion-tensor MR imaging and fiber tractography: a new method of describing aberrant fiber connections in developmental CNS anomalies. , 2005, Radiographics : a review publication of the Radiological Society of North America, Inc.

[3]  K. Tory,et al.  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. , 2007, Journal of the American Society of Nephrology : JASN.

[4]  Colin A. Johnson,et al.  Jouberin localizes to collecting ducts and interacts with nephrocystin-1. , 2008, Kidney international.

[5]  W. G. Kelly,et al.  Functional genomic analysis of the ADP‐ribosylation factor family of GTPases: phylogeny among diverse eukaryotes and function in C. elegans , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  M. Scott,et al.  Control of Neuronal Precursor Proliferation in the Cerebellum by Sonic Hedgehog , 1999, Neuron.

[7]  Paul M. Jenkins,et al.  Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons , 2007, Proceedings of the National Academy of Sciences.

[8]  R. Tusa,et al.  "Joubert Syndrome" Revisited: Key Ocular Motor Signs With Magnetic Resonance Imaging Correlation , 1997, Journal of child neurology.

[9]  N. Katsanis,et al.  Ciliary function and Wnt signal modulation. , 2008, Current topics in developmental biology.

[10]  I. Glass,et al.  Joubert syndrome (and related disorders) (OMIM 213300) , 2007, European Journal of Human Genetics.

[11]  A. Schier,et al.  Cilia-driven fluid flow in the zebrafish pronephros, brain and Kupffer's vesicle is required for normal organogenesis , 2005, Development.

[12]  A. Joyner,et al.  Morphogenetic and Cellular Movements that Shape the Mouse Cerebellum Insights from Genetic Fate Mapping , 2005, Neuron.

[13]  O. A. Cabello,et al.  Cilia Proteins Control Cerebellar Morphogenesis by Promoting Expansion of the Granule Progenitor Pool , 2007, The Journal of Neuroscience.

[14]  J. Naggert,et al.  A mouse model for Meckel syndrome type 3. , 2009, Journal of the American Society of Nephrology : JASN.

[15]  I. Glass,et al.  Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome , 2007, Nature Genetics.

[16]  Kyoko Takano,et al.  Cerebellar and brainstem involvement in familial juvenile nephronophthisis type I. , 2003, Pediatric neurology.

[17]  J. Calogero Vermian agenesis and unsegmented midbrain tectum. Case report. , 1977, Journal of neurosurgery.

[18]  E. Bertini,et al.  NPHP1 gene deletion is a rare cause of Joubert syndrome related disorders , 2005, Journal of Medical Genetics.

[19]  Dorothy A. Thompson,et al.  Joubert syndrome: long‐term follow‐up , 2004, Developmental medicine and child neurology.

[20]  Xingshun Xu,et al.  Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice. , 2008, The Journal of clinical investigation.

[21]  K. Anderson,et al.  Cilia and developmental signaling. , 2007, Annual review of cell and developmental biology.

[22]  A. Joyner,et al.  Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling , 2008, Development.

[23]  P. Satir,et al.  The primary cilium coordinates signaling pathways in cell cycle control and migration during development and tissue repair. , 2008, Current topics in developmental biology.

[24]  A. Joyner,et al.  Sonic hedgehog regulates Gli activator and repressor functions with spatial and temporal precision in the mid/hindbrain region , 2006, Development.

[25]  B. Maria,et al.  Neurobehavioral Development in Joubert Syndrome , 1998, Journal of child neurology.

[26]  Wallace F. Marshall,et al.  Chapter 1 Basal Bodies , 2008 .

[27]  A. Swaroop,et al.  In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. , 2006, Human molecular genetics.

[28]  T. Strachan,et al.  Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination , 2003, Nature Genetics.

[29]  H. Agarwal,et al.  Joubert`S syndrome , 2006 .

[30]  Bethan E. Hoskins,et al.  Triallelic Inheritance in Bardet-Biedl Syndrome, a Mendelian Recessive Disorder , 2001, Science.

[31]  C. Antignac,et al.  Hypoplasies vermiennes avec atteintes extracérébrales (rétine, rein, foie) : des syndromes difficiles à classerCerebellar vermis hypoplasias with extracerebral involvement (retina, kidney, liver): difficult to classify syndromes. , 2001 .

[32]  D. Yousem Invited Commentary • Authors' Response , 2005 .

[33]  Z. Rumboldt,et al.  Absence of decussation of the superior cerebellar peduncles in patients with Joubert syndrome , 2008, American journal of medical genetics. Part A.

[34]  A. Joyner,et al.  Gli 3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf 8 signaling , 2022 .

[35]  D. Theriaque,et al.  Quantitative Assessment of Brainstem Development in Joubert Syndrome and Dandy-Walker Syndrome , 2001, Journal of child neurology.

[36]  E. Boltshauser,et al.  Follow-up in children with Joubert syndrome. , 1997, Neuropediatrics.

[37]  M. Eccles,et al.  Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome , 2005, Pediatric Nephrology.

[38]  H. T. ten Donkelaar,et al.  A case of Joubert's syndrome with extensive cerebral malformations. , 2000, Clinical neuropathology.

[39]  B. Maria,et al.  Clinical Features and Revised Diagnostic Criteria in Joubert Syndrome , 1999, Journal of child neurology.

[40]  F. Chang,et al.  Prenatal diagnosis of Joubert syndrome complicated with encephalocele using two-dimensional and three-dimensional ultrasound. , 1999, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[41]  J. Reiter,et al.  The primary cilium at the crossroads of mammalian hedgehog signaling. , 2008, Current topics in developmental biology.

[42]  B. Maria,et al.  The face of Joubert syndrome: A study of dysmorphology and anthropometry , 2007, American journal of medical genetics. Part A.

[43]  V. Malhotra,et al.  CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease. , 2008, Developmental cell.

[44]  N. Hirokawa,et al.  Mechanism of Nodal Flow: A Conserved Symmetry Breaking Event in Left-Right Axis Determination , 2005, Cell.

[45]  O. Ljungberg,et al.  Joubert syndrome associated with Leber amaurosis and multicystic kidneys. , 1993, American journal of medical genetics.

[46]  J. Gleeson,et al.  CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium. , 2008, Human molecular genetics.

[47]  I. Glass,et al.  Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior–Løken syndrome , 2007, Journal of Medical Genetics.

[48]  R. Tusa,et al.  Ocular and Oculomotor Signs in Joubert Syndrome , 1999, Journal of child neurology.

[49]  Nicholas Katsanis,et al.  The ciliopathies: an emerging class of human genetic disorders. , 2006, Annual review of genomics and human genetics.

[50]  Madeline A. Lancaster,et al.  Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome , 2006, Nature Genetics.

[51]  R. Lewis,et al.  Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome , 2008, Nature Genetics.

[52]  F. Andermann,et al.  Familial Agenesis of the Cerebellar Vermis: A Syndrome of Episodic Hyperpnea, Abnormal Eye Movements, Ataxia, and Retardation , 1999, Neurology.

[53]  J. Iverson,et al.  Oromotor and Communication Findings in Joubert Syndrome: Further Evidence of Multisystem Apraxia , 2006, Journal of child neurology.

[54]  J. Reiter,et al.  The primary cilium at the crossroads of mammalian hedgehog signaling. , 2008, Current topics in developmental biology.

[55]  Lee Niswander,et al.  Hedgehog signalling in the mouse requires intraflagellar transport proteins , 2003, Nature.

[56]  P. Satir,et al.  Overview of structure and function of mammalian cilia. , 2007, Annual review of physiology.

[57]  C. Antignac,et al.  Evidence of oligogenic inheritance in nephronophthisis. , 2007, Journal of the American Society of Nephrology : JASN.

[58]  T. Meitinger,et al.  Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. , 2006, American journal of human genetics.

[59]  C. Antignac,et al.  [Cerebellar vermis hypoplasia with extracerebral involvement (retina, kidney, liver): difficult to classify syndromes]. , 2001, Archives de pediatrie : organe officiel de la Societe francaise de pediatrie.

[60]  É. Straub,et al.  Familial juvenile nephronophthisis with hepatic fibrosis and neurocutaneous dysplasia. , 1980, Helvetica paediatrica acta.

[61]  L. Peltonen,et al.  Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. , 2008, American journal of human genetics.

[62]  N. Hirokawa,et al.  Randomization of Left–Right Asymmetry due to Loss of Nodal Cilia Generating Leftward Flow of Extraembryonic Fluid in Mice Lacking KIF3B Motor Protein , 1999, Cell.

[63]  Colin A. Johnson,et al.  Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. , 2007, American journal of human genetics.

[64]  F. Hildebrandt,et al.  A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1 , 1997, Nature Genetics.

[65]  G. Mollet,et al.  Characterization of the nephrocystin/nephrocystin-4 complex and subcellular localization of nephrocystin-4 to primary cilia and centrosomes. , 2005, Human molecular genetics.

[66]  M. King,et al.  Joubert's syndrome with retinal dysplasia: neonatal tachypnoea as the clue to a genetic brain-eye malformation. , 1984, Archives of disease in childhood.

[67]  C. Walsh,et al.  Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome , 2004, Nature Genetics.

[68]  J. García-Verdugo,et al.  Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. , 2008, Developmental biology.

[69]  Colin A. Johnson,et al.  The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. , 2007, Human molecular genetics.

[70]  E. Bertini,et al.  CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. , 2007, American journal of human genetics.

[71]  Colin A. Johnson,et al.  The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat , 2006, Nature Genetics.

[72]  Carsten Bergmann,et al.  Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel‐Gruber syndrome , 2008, Human mutation.

[73]  W. Huttner,et al.  Intraflagellar transport protein 172 is essential for primary cilia formation and plays a vital role in patterning the mammalian brain. , 2009, Developmental biology.

[74]  Colin A. Johnson,et al.  The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome , 2007, Nature Genetics.

[75]  W. Marshall,et al.  Basal bodies platforms for building cilia. , 2008, Current topics in developmental biology.

[76]  J. Rosenbaum,et al.  Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. , 2008, Current topics in developmental biology.

[77]  S. Fisher,et al.  Dissection of epistasis in oligogenic Bardet–Biedl syndrome , 2006, Nature.

[78]  N. Katsanis,et al.  Human genetics and disease: Beyond Mendel: an evolving view of human genetic disease transmission , 2002, Nature Reviews Genetics.

[79]  Mark S. Miller,et al.  A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney , 2004, Development.

[80]  A. Verloes,et al.  Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis. , 1989, American journal of medical genetics.

[81]  Y. Saijoh,et al.  Determination of left–right patterning of the mouse embryo by artificial nodal flow , 2002, Nature.

[82]  H. Hamada,et al.  The left-right axis in the mouse: from origin to morphology , 2006, Development.

[83]  E. Bertini,et al.  Mutations in the CEP290 gene, encoding a centrosomal protein, cause pleiotropic forms of Joubert Syndrome , 2006 .

[84]  Johanna Andrae,et al.  Role of platelet-derived growth factors in physiology and medicine. , 2008, Genes & development.

[85]  H. Kayserili,et al.  Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. , 2004, American journal of human genetics.

[86]  T. Loenneker,et al.  Diffusion Tensor Imaging in Joubert Syndrome , 2007, American Journal of Neuroradiology.

[87]  A. Weiss,et al.  Eye movement abnormalities in Joubert syndrome. , 2009, Investigative ophthalmology & visual science.

[88]  A. Reiss,et al.  Autistic features in Joubert syndrome: A genetic disorder with agenesis of the cerebellar vermis , 1991, Biological Psychiatry.

[89]  H. Clevers Wnt/beta-catenin signaling in development and disease. , 2006, Cell.

[90]  H. Zentgraf,et al.  Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. , 2006, Journal of the American Society of Nephrology : JASN.

[91]  M. Tang,et al.  Targeted disruption of Nphp1 causes male infertility due to defects in the later steps of sperm morphogenesis in mice. , 2008, Human molecular genetics.

[92]  J. Rosenbaum,et al.  Chapter Two Intraflagellar Transport (IFT) , 2008 .

[93]  D. Taylor,et al.  A syndrome of congenital retinal dystrophy and saccade palsy--a subset of Leber's amaurosis. , 1984, The British journal of ophthalmology.

[94]  E. Boltshauser,et al.  Joubert Syndrome: Episodic Hyperpnea, Abnormal Eye Movements, Retardation and Ataxia, Associated with Dysplasia of the Cerebellar Vermis , 1977, Neuropadiatrie.

[95]  L. Al-Gazali,et al.  Joubert's syndrome: new cases and review of clinicopathologic correlation. , 1999, Pediatric neurology.

[96]  A. Calame,et al.  Hidden Intelligence of a Multiply Handicapped Child with Joubert Syndrome , 1990, Developmental medicine and child neurology.

[97]  Carolyn M Hutter,et al.  CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. , 2008, American journal of human genetics.

[98]  Erich A. Nigg,et al.  Cep164, a novel centriole appendage protein required for primary cilium formation , 2007, The Journal of cell biology.

[99]  W. Dobyns,et al.  Cerebello-oculo-renal syndromes including Arima, Senior-Löken and COACH syndromes: more than just variants of Joubert syndrome. , 1999, American journal of medical genetics.

[100]  I. Glass,et al.  AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome , 2005, Journal of Medical Genetics.

[101]  R. Dom,et al.  Variability of outcome in Joubert syndrome. , 1985, Neuropediatrics.

[102]  M. Dorschner,et al.  Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis) , 2009, Journal of Medical Genetics.

[103]  B. J. Williams,et al.  Autism and Autistic Behavior in Joubert Syndrome , 1999, Journal of child neurology.

[104]  B. Maria,et al.  Joubert syndrome is not a cause of classical autism , 2005, American journal of medical genetics. Part A.

[105]  K. Arima,et al.  Renal disease in Arima syndrome is nephronophthisis as in other Joubert‐related Cerebello–oculo–renal syndromes , 2004, American journal of medical genetics. Part A.

[106]  H. Brunner,et al.  From syndrome families to functional genomics , 2004, Nature Reviews Genetics.

[107]  Colin A. Johnson,et al.  Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. , 2008, American journal of human genetics.

[108]  I. Glass,et al.  The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. , 2004, American journal of human genetics.

[109]  N. Hirokawa,et al.  Nodal Flow and the Generation of Left-Right Asymmetry , 2006, Cell.

[110]  F. Hildebrandt,et al.  Nephronophthisis-associated ciliopathies. , 2007, Journal of the American Society of Nephrology : JASN.

[111]  P. Beales,et al.  Bardet–Biedl syndrome: beyond the cilium , 2007, Pediatric Nephrology.

[112]  T. Matsuzaka,et al.  Cerebro-Oculo-Hepato-Renal Syndrome (Arima's Syndrome): A Distinct Clinocopathological Entity , 1986, Journal of child neurology.

[113]  I. Glass,et al.  Molar tooth sign of the midbrain–hindbrain junction: Occurrence in multiple distinct syndromes , 2004, American journal of medical genetics. Part A.

[114]  Yan Liu,et al.  The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4 , 2006, Nature Genetics.

[115]  Tamara Caspary,et al.  The graded response to Sonic Hedgehog depends on cilia architecture. , 2007, Developmental cell.

[116]  Arif O. Khan,et al.  Ophthalmic features of Joubert syndrome. , 2008, Ophthalmology.

[117]  V. Sheffield,et al.  A Core Complex of BBS Proteins Cooperates with the GTPase Rab8 to Promote Ciliary Membrane Biogenesis , 2007, Cell.

[118]  Colin A. Johnson,et al.  The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. , 2007, American journal of human genetics.

[119]  E. Boltshauser,et al.  Uncommon Syndromes of Cerebellar Vermis Aplasia. I: Joubert Syndrome , 1978, Developmental medicine and child neurology.

[120]  P. Barth,et al.  Joubert syndrome: a clinical and pathological description of an affected male and a female fetus from the same sibship. , 1991, American journal of medical genetics.

[121]  M. Baraitser,et al.  Joubert syndrome: a review. , 1992, American journal of medical genetics.

[122]  H. Yost,et al.  Kupffer's vesicle is a ciliated organ of asymmetry in the zebrafish embryo that initiates left-right development of the brain, heart and gut , 2005, Development.

[123]  M. Pembrey,et al.  Follow-up and diagnostic reappraisal of 75 patients with Leber's congenital amaurosis. , 1989, American journal of ophthalmology.

[124]  S. Targan,et al.  Development of hydrocephalus in a patient with Joubert syndrome. , 2004, Journal of Postgraduate Medicine.

[125]  J. Pearce,et al.  The prenatal diagnosis of joubert's syndrome of familial agenesis of the cerebellar vermis , 1984, Prenatal diagnosis.

[126]  A. Djukic,et al.  [Joubert's syndrome]. , 1989, Srpski arhiv za celokupno lekarstvo.

[127]  A. Munnich,et al.  Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype , 2007, Human mutation.

[128]  A. C. Casamassima,et al.  A new syndrome with features of the Smith-Lemli-Opitz and Meckel-Gruber syndromes in a sibship with cerebellar defects. , 1987, American journal of medical genetics.