Human Molecular Genetics

Human Molecular Genetics 2005 14(Review Issue 2):R235-R242; doi:10.1093/hmg/ddi264

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Genetic basis of Joubert syndrome and related disorders of cerebellar development

Carrie M. Louie¹ and Joseph G. Gleeson^2,*

¹Biomedical Sciences Graduate Program and ²Neurogenetics Laboratory, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0691, USA

^* To whom correspondence should be addressed. Tel: +1 8588223535; Fax: +1 8588221021; Email: jogleeson{at}ucsd.edu

Received July 1, 2005; Accepted July 8, 2005

	ABSTRACT

TOP ABSTRACT CLINICAL FEATURES NEUROPATHOLOGY OVERVIEW OF CEREBELLAR... FUNCTIONAL GENE CANDIDATES POSITIONAL CLONING RELATED DISORDERS THE CILIA CONNECTION CONCLUSIONS REFERENCES

 
Over three decades have passed since Marie Joubert described the original proband for Joubert syndrome, a rare neurological disorder featuring absence of the cerebellar vermis (i.e. midline). Efforts at deciphering the molecular basis for this disease have been complicated by the clinical and genetic heterogeneity as well as extensive phenotypic overlap with other syndromes. However, progress has been made in recent years with the mapping of three genetic loci and the identification of mutations in two genes, AHI1 and NPHP1. These genes encode proteins with some shared functional domains, but their role in brain development is unclear. Clues may come from studies of related syndromes, including Bardet–Biedl syndrome and nephronophthisis, for which all of the encoded proteins localize to primary cilia. The data suggest a tantalizing connection between intraflagellar transport in cilia and brain development.

	CLINICAL FEATURES

TOP ABSTRACT CLINICAL FEATURES NEUROPATHOLOGY OVERVIEW OF CEREBELLAR... FUNCTIONAL GENE CANDIDATES POSITIONAL CLONING RELATED DISORDERS THE CILIA CONNECTION CONCLUSIONS REFERENCES

 
Joubert syndrome (JS) is an autosomal recessive neurodevelopmental disorder, which is characterized by the molar tooth malformation (MTM), a complex brainstem malformation that reflects aplasia or marked hypoplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deepened interpeduncular fossa that is apparent on axial MRI at the midbrain–hindbrain junction (Fig. 1)(1). Clinically, classic JS is associated with neonatal hypotonia (loss of muscle tone), ataxia, developmental delay, mental retardation, and often neonatal apnea/hyperpnea (irregular breathing) and/or ocular motor apraxia (difficulties in initiating rapid horizontal eye movements—saccades)(2–4). Autistic features have also been reported as a relatively common component of JS (5,6).

View larger version (106K): [in this window] [in a new window]   Figure 1. T1-weighted MRI showing the characteristic ‘molar tooth’ malformation (arrows) and vermis hypoplasia (arrowhead).

 
None of these features alone is diagnostic of JS, however, and in more recent years, it has become obvious that JS is a part of a spectrum of disorders involving vermis hypoplasia and the MTM. Some of these include COACH (OMIM 216360 [OMIM] ), referring to characteristic hallmarks of cerebellar vermis hypoplasia, oligophrenia (mental impairment), congenital ataxia, ocular coloboma and hepatic fibrosis (7–9); and Váradi Papp or orofaciodigital VI syndrome (OMIM 277170 [OMIM] ), defined by midline facial or hand abnormalities (7,10).

Varying degrees of extra-CNS involvement have further complicated diagnosis, including ocular colobomas, postaxial polydactyly, liver fibrosis, cystic dysplastic kidneys, retinopathy and/or nephronophthisis (NPHP) (7,11–17). These features significantly overlap with other disorders with cerebello-oculo-renal involvement, most notably NPHP; the significance of this relationship is strengthened by the identification of deletions of NPHP1, a gene commonly mutated in NPHP in a subset of JS patients (18,19).

	NEUROPATHOLOGY

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There have been few detailed studies of neuropathology in JS patients, but various abnormalities have been identified as common to JS, affecting a number of systems in the midbrain and hindbrain. The most striking is the absence of the cerebellar vermis, thought to be important for control of balance, regulation of muscle tone and saccadic (rapid) eye movements, although it should be noted that many lesions of the cerebellum could have this effect. The dentate nuclei, the major source of cerebellar output to the cerebral cortex, are fragmented into islands. Malformation of various pontine and medullary structures, including the basis pontis, reticular formation, inferior olivary, dorsal column and solitary tract nuclei, have been reported, which may explain the respiratory defects in JS (2,20). Heterotopias of Purkinje-like neurons have been described in some patients, suggesting a migration defect (2). Defects of proliferation are also likely, considering the absence of the vermis as well as the report of diminished density of granule neurons (2).

An interesting abnormality is the absence of decussation both of the superior cerebellar peduncles and of the corticospinal tracts at the medullary pyramids, which suggests that JS patients may have a defect of axon guidance. The pyramidal decussation is the site where the majority of corticospinal tracts cross at the midline (21), and defects in this event suggest that JS patients may display altered brain wiring. Indeed, a study on fMRI patterns reveals more bilateral activation in a JS patient versus a control, which is consistent with a defect of neural connectivity (22). In total, the pathology of JS seems to reflect abnormalities in a variety of events, suggesting that the genes involved are acting early in brain development.

	OVERVIEW OF CEREBELLAR DEVELOPMENT

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Understanding of cerebellar development provides some insights into the pathogenesis of JS. The cerebellum arises from both the mesencephalic and rhombencephalic vesicles of the neural tube and develops over a relatively long period of time between early embryogenesis and late childhood (23,24). Development of the cerebellum can be described in four basic stages.

In the first stage, characterization of cerebellar territory occurs at the midbrain–hindbrain boundary. Transplantation studies in chicken and mouse have found that the isthmus organizer (IsO), a region corresponding to the midbrain–hindbrain boundary expression, is crucial for specifying midbrain and cerebellar structures (25). At the isthmus, restricted expression of secreted factors, such as fibroblast growth factor 8, FGF8 (26,27) and Wnt1, the mammalian homolog of Drosophila wingless gene (28), as well as homeobox proteins En1 and En2 (29,30) and paired box genes Pax2 and Pax5 (31,32) are required for early specification of midbrain and hindbrain structures (33). In the second stage, two compartments for cell proliferation are formed. Purkinje cells and cells of the deep cerebellar nuclei are generated in the roof of the fourth ventricle (34,35), and granule cell precursors, as well as cells of the precerebellar nuclei are formed in the rhombic lip (36). Development of Purkinje cells is not well understood, but they are known to secrete Sonic hedgehog which regulates proliferation of granule cells (37,38). By this time point, granule neuron precursors express a number of markers, Math1, nestin, zipro1/RU49 and Zic genes 1, 2 (39–42). Purkinje cells migrate radially to their final positions, whereas granule neurons migrate over the surface of the developing cerebellum, forming the external granule layer (EGL) (Fig. 2A and B). In the third stage, cells of the EGL migrate inward along the processes of Bergman glia to their final position in the internal granular layer (IGL) (43). Finally, cerebellar circuitry is established and further differentiation occurs. The lower portion of the rhombic lip also gives rise to cells of the precerebellar nuclei such as the inferior olivary nuclei, which migrate to positions in the brainstem (44).

View larger version (40K): [in this window] [in a new window]   Figure 2. Schematic overview of cerebellar development. (A) Diagram of dorsal view of cerebellar anlage showing migration from the rhombic lip over the surface of the neural tube. Granule neuron precursors migrate rostrally, whereas precursors of precerebellar nuclei migrate ventrally. (B) Diagram of cross-section through the anlage showing radial migration of Purkinje cell precursors from the ventricular zone (VZ) and tangential migration of granule cells from the rhombic lip (RL). (C) ‘Time-lapse’ diagram of granule neuron migration. Granule cell precursors proliferate in the outer EGL. Postmitotic cells move into the inner EGL and extend parallel axons and a descending process prior to migration through the molecular layer (ML) along fibers of Bergman glia (data not shown), until settlement in the IGL. Human developmental time point indicated by wk (refers to prenatal) or yr (refers to postnatal).

 

	FUNCTIONAL GENE CANDIDATES

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Because the pathology of JS suggests defects of early cerebellar development, particularly of structures derived from the primitive isthmus (45), genes involved in cerebellar patterning at the IsO have been tested as candidate genes, especially those with comparable phenotypes in mouse models. The swaying mouse, which was shown to have a truncation mutation of Wnt1, has a phenotype reminiscent of JS, i.e. ataxia, and agenesis of cerebellar structures (46). Mutant alleles of Fgf8, En1 and En2 also result in cerebellar abnormalities. A hypomorphic allele of Fgf8 was shown to cause deletion of midbrain and hindbrain structures (47). En1 and En2 mice also manifest absent or abnormal cerebellar structures (48,49). Mutations in these genes, however, could not be identified in JS patients screened thus far, suggesting that they are not likely to be a common cause of JS (50,51).

The ZIC (zinc fingers in the cerebellum) family of transcription factors were named for their exclusively cerebellar expression in adults. Embryonically, they are more widely distributed and have been implicated in a variety of developmental functions (52,53). Zic1 mutant mice have hypoplastic cerebella that are missing anterior lobules of the vermis (54). They also have behavioral deficits of ataxia and hypotonia, as in patients with JS, and were thought to be a good model for the disease (55). However, in an analysis of 35 JS pedigrees, ZIC1 was also excluded as a causative gene (56). In fact, heterozygous mutations in ZIC1 and ZIC4 have been reported to be a cause of the related, but distinct Dandy–Walker malformation, characterized by hypoplasia and upward rotation of the vermis, cystic enlargement of the fourth ventricle and often hydrocephalus (57).

	POSITIONAL CLONING

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The lack of success with functional candidate screening suggests that novel genes are involved in JS and that linkage mapping may be more fruitful. Linkage studies for JS genes have relied on homozygosity mapping in consanguineous families, a more powerful method for detecting linkage for rare disease genes where large families may not be available (58).

JS is genetically heterogeneous and so far three genetic loci have been mapped to 9q34.3 (JBTS1: OMIM 213300 [OMIM] ), 11p12–q13.3 (JBTS2: OMIM 608091 [OMIM] ) and 6q23 (JBTS3: 608629) (58–60). Because there are families that do not map to any of these loci, there are likely to be more genes involved. Genotype–phenotype analysis reveals differences at the mapped loci (61). JBTS1 appears to represent the classic Joubert phenotype of pure cerebellar and midbrain–hindbrain junction involvement, although the JBTS3 gene is also associated with cerebral cortical abnormalities, most notably polymicrogyria. JBTS2, in addition to classical JS features, is associated with a variety of other organ systems, involving kidney, eye and liver. Of the known loci, only JBTS3 has been cloned (62,63), with mutations identified in AHI1. AHI1, the Abelson helper integration 1 gene, was initially identified as a common helper provirus integration site (64) and only more recently found to encode a protein (65). Jouberin, encoded by AHI1, contains seven WD40 repeats, an SH3 domain, potential SH3 binding sites and an N-terminal coiled–coiled domain. Numerous putative casein kinase, tyrosine kinase and protein kinase C phosphorylation sites can also be detected in the sequence (65). The mRNA is widely expressed in the brain at a range of time points (62,63). The domain structure suggests that Jouberin functions in signal transduction, perhaps as an adaptor molecule, but little is known about AHI1 and how it might be involved in the pathogenesis of JS. WD40 domains have been found in proteins involved in a variety of functions including signal transduction, RNA processing, transcriptional regulation, cytoskeleton assembly, vesicle trafficking and cell division (66). Similarly, SH3 domains are a common feature on signaling molecules, involved in numerous pathways (67).

	RELATED DISORDERS

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The range of the JS phenotype often involves systems outside the CNS and significantly overlaps with other disorders, for some of which, genes have been identified. The similarities in phenotype suggest that shared or similar pathways are affected in these disorders. Studying the functions of these genes may contribute to our understanding of JS. Interestingly, most of these genes have been shown to function in the cilia and/or intraflagellar transport (IFT).

NPHP and mutations in NPHP1
NPHP is a kidney disorder that represents the most common heritable cause of end-stage renal disease in children and is characterized by tubular atrophy, interstitial fibrosis and development of renal cysts. There are five genes (nephrocystin 1–5) known to cause several forms of NPHP (68). Juvenile NPHP is most often caused by mutations in NPHP1, encoding nephrocystin (69). The most common mutation is a homozygous deletion that spans three contiguous genes. A subset of JS patients selected on the basis of retinal and/or kidney involvement were recently screened for mutations and identified the common NPHP1 deletion as a rare cause of JS (18,19). Conversely, cerebellar malformations have been identified in patients diagnosed with NPHP (70).

All of the NPHP genes have been localized to primary cilia of renal epithelial cells and largely at the basal bodies, modified centrioles that form the base of cilia (71–75). NPHP2, encoding inversin, a known cilia-related protein mutated in infantile NPHP, was the first direct evidence of involvement of cilia function in NPHP (73). In invs mutant mice, the phenotype includes large kidney cysts and abnormalities in left–right patterning, situs inversus, in which organs have reverse orientation (76). This unusual phenotype is due to abnormalities of leftward nodal flow, generated by monocilia that line the ventral surface of the embryonic node (77,78). Furthermore, nephrocystin-1 and -4 homologs in Caenorhabditis elegans, which do not have a renal system, have been localized exclusively to ciliated sensory neurons, suggesting that they have conserved roles in ciliary function (79).

Nephrocystins have also been identified in other cellular compartments that implicate them in other functions including cell matrix signaling and cell division. NPHP1 and NPHP4 have been demonstrated to interact and form complexes with focal adhesion and cell–cell adherens junction proteins and localize to the subcortical region close to cell–cell junctions in polarized renal epithelial cells, as well as to the centrosome in confluent cells (74). Inversin was shown to interact with N-cadherin and catenins at the plasma membrane and a shorter isoform has been detected in the nucleus where it interacts with ß-catenin in a proximal tubule kidney cell line (80). It has also been localized to the centrosome in early prophase and to mitotic spindle poles in metaphase, where it interacts with the anaphase promoting complex 2, Apc2 (81). Intriguingly, a recent study suggests that inversin may be involved in the Wnt pathway by switching off the canonical pathway at the level of Dvl1 (82).

The phenotypes of JS and NPHP also overlap with that of several other disorders for which the MTM can be identified as a component. Seniör–Loken syndrome (OMIM 266900 [OMIM] ) consists of the MTM, and NPHP with retinal aplasia like Leber congenital amaurosis, and has been associated with mutations in NPHP1 and NPHP4 (83). The recently identified nephrocystin-5 or ICQB1, which shares functional domains with inversin, appears to be the most common cause of Seniör–Loken, further supporting the connection between the MTM and the NPHP genes (75).

Also closely related is Dekaban–Arima syndrome (OMIM 243910 [OMIM] ), associated with vermis aplasia, retinopathy and cystic dysplastic kidneys (84). This syndrome has been traditionally distinguished from Seniör–Loken by its less severe kidney disease, but more recent analysis suggests that the renal involvement in DAS is indistinguishable from NPHP, making it less distinct from the other cerebello-oculo-renal disorders that overlap with JS (7,11,85).

Bardet–Biedl syndrome and IFT
Bardet–Biedl syndrome (BBS: OMIM 209900 [OMIM] ) is characterized by obesity, mental retardation, polydactyly, gonadal malformation, retinal dystrophy and renal dysfunction (86–88). Neurological malformations are unusual, but cerebellar abnormalities have been reported in the literature (89,90) and, in particular, a case of CVH has been documented in a patient with BBS (91). Although not reported to be present, we found clear evidence of the MTM in the MRI data for this patient, suggesting a link between BBS and JS. Eight genes, BBS1–BBS8, have been identified to date and all of the encoded proteins have been localized to cilia and/or implicated in ciliary function and assembly, including cytoskeletal reorganization and cytokinesis (88,92–100). In particular, BBS4 has been associated with components of IFT (101), a microtubule-dependent mechanism by which components are trafficked during assembly and maintenance of cilia and flagella (102–105). IFT was discovered first in Chlamydomonas (106), but has subsequently been shown to be conserved in other species (107,108). Loss-of-function studies in C. elegans have also shown the requirement of BBS genes in this process. Mutations in bbs-7 and bbs-8 orthologs result in shortened cilia with impaired chemosensory ability and almost complete loss of movement of some known IFT molecules (109).

The link to IFT is especially interesting in light of the recent implication of IFT proteins in the hedgehog-signaling pathway, critical for many developmental processes. In an ENU mutagenesis screen for phenotypes resembling defective hedgehog signaling in mouse, Huangfu et al. (110) demonstrated the requirement for IFT proteins (IFT88, IFT172) in normal hedgehog signaling downstream of its receptor Patched. Liu et al. (111) further show that they act upstream of the proteolytic processing of Gli proteins, the transcriptional effectors of the Hh pathway. Although it is implied that cilia function is important for these pathways, it still remains to be shown whether cilia are directly required or whether these genes are simply performing multiple distinct functions within the cell.

	THE CILIA CONNECTION

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The current evidence from related diseases and their causative genes suggest a very surprising role for cilia in brain development. Although direct evidence is not yet available for a ciliary mechanism of pathogenesis of JS, it is tempting to consider the potential, especially in light of the growing evidence for primary cilia function in disease and development.

Consistent with this, 9+0 primary cilia have been reported in a large number of cell types in the brain (112–114), including Purkinje and granule cells of the cerebellum, where they are found protruding between extracellular spaces, even during proliferative phases (115,116). In fact, cilia are present in a majority of vertebrate cells and can be very structurally and functionally heterogeneous. Evidence is accumulating for the function of primary cilia as flow mechanosensory signaling modules in renal epithelial cells (117,118), but exactly how non-motile primary cilia are functioning in the brain is not known.

Specific receptors have been localized to subpopulations of neuronal cilia, i.e. somatostatin receptor 3 (119,120) and serotonin receptor 6 (121). This suggests that cerebellar cilia may express other specific receptors and that they are functioning to transduce signals, perhaps from morphogens like Wnts or Shh, to regulate proliferation or differentiation. In this model, Jouberin and nephrocystin would be functioning either as downstream molecules in the signaling cascade or possibly through IFT mechanisms, bringing necessary components of the pathway to the signal (Fig. 3). Indeed, other cilia-associated genes such as inversin have already been implicated in cell cycle and/or transcriptional regulation. It remains to be shown whether Jouberin, NPHP1 and other JS genes to be identified, function similarly.

View larger version (18K): [in this window] [in a new window]   Figure 3. Model for cilia-based signaling in cerebellar development and potential role of jouberin (JBN) and nephrocystin (NPC). Cilia are present on most if not all cells of the cerebellum, including cells of the EGL and migrating neurons. JBN and NPC may be required for transduction of morphogenic signals, possibly through cilia or IFT-based mechanisms, to regulate proliferation or differentiaion.

 

	CONCLUSIONS

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JS is a part of a spectrum of developmental disorders with a complex midbrain–hindbrain malformation as well as involvement of other systems—renal, retinal and/or hepatic. Mutations of AHI1 have recently been shown to cause a form of JS, but the function of this gene is currently unknown. However, it is interesting to find that genes associated with related disorders all seem to encode proteins involved in cilia function or assembly, suggesting an interesting link between cilia and cerebellar development. It is tempting to speculate that genes involved in JS may also be involved in cilia or in mediating cilia-dependent signals.

	ACKNOWLEDGEMENTS

 
We would like to thank Jennifer Silhavy, Sarah Marsh and Madeline Lancaster for helpful comments. The work on Joubert syndrome in the Gleeson lab is funded by grants from the March of Dimes, the NINDS and the Burroughs Wellcome Fund in Translational Research. C.M.L. is supported by the Genetics Training Grant at the University of California, San Diego, USA.

Conflict of Interest statement. None declared.

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