Joubert syndrome (WP4656)

Homo sapiens

Open in new tab Open in NDEx
Download PNG Download SVG Download JSON Download GPML Learn more about Downloads
Joubert syndrome (JS) is a rare hereditary disorder that is classified as a ciliopathy, and is caused by mutations occurring in genes essential for the development and proper functioning of primary cellular cilia. These hair-like structures located on the cell membrane are responsible for detecting and relaying external signals to the interior of the cell. The defining JS feature is the molar tooth sign (MTS), which is the particular manner in which a characteristic malformation of midbrain appears in radiological imaging, and which causes delays in both intellectual and motor development. A visual representation of the pathways underlying JS pathogenesis was synthesized, which might provide a more complete understanding of the disease, possibly aiding in better diagnosis and more successful treatment. Data collection on the genes, pathways and interactions involved was done through a literature search in combination supported by online databases such as OMIM, STRING and GeneMANIA. The pathway was created using PathVisio version 3.3.0. Nodes were annotated using the appropriate Ensembl, ChEBI, or Uniprot-TrEMBL identifiers and standardized MIM notation was used to visualize the interactions between them. A final pathway containing 88 unique nodes and 71 interactions was created. The pathway highlights three functional or structural areas of the primary cilium that appear to play important roles in JS pathogenesis, namely the basal body or centriole, the transition zone and ciliary trafficking. Furthermore, two specific complexes seem to be of particular interest; the B9 ciliary complex and the centriolar satellite contain eight and three JS-associated protein respectively. Lastly, the ARL13B-PDE6D-INPP5E signaling network ensures the proper functioning of INPP5E, and enzyme that converts lipid ciliary membrane components. All three proteins have been found to be mutated in JS patients.

Authors

Anna De Brouwer , Egon Willighagen , Friederike Ehrhart , and Eric Weitz

Activity

last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organisms

Homo sapiens

Communities

Rare Diseases

Annotations

Pathway Ontology

disease pathway signaling pathway

Disease Ontology

Joubert syndrome

Participants
Query Drugst.One

Label Type Compact URI Comment
GDP Metabolite chebi:17552
PtdIns4P Metabolite chebi:17526
NBS Metabolite chebi:53174
GDP Metabolite chebi:17552
GDP Metabolite chebi:17552
PtdIns(3,4,5)P3 Metabolite chebi:16618
GMP Metabolite chebi:16356
PtdIns(4,5)P2 Metabolite chebi:18348
PtdIns(3,4)P2 Metabolite chebi:84247
cGMP Metabolite chebi:16356
GTP Metabolite chebi:37565
Calmodulin Metabolite chebi:3324
GTP Metabolite chebi:37565
GTP Metabolite chebi:37565
GTP Metabolite chebi:37565
TMEM17 GeneProduct ensembl:ENSG00000186889
TMEM67 GeneProduct ensembl:ENSG00000164953
TMEM216 GeneProduct ensembl:ENSG00000187049
KIAA0586 GeneProduct ensembl:ENSG00000100578
DVL3 GeneProduct ensembl:ENSG00000161202
RAB3IP GeneProduct ensembl:ENSG00000127328
SUFU GeneProduct ensembl:ENSG00000107882
ATF4 GeneProduct ensembl:ENSG00000128272
CEP97 GeneProduct ensembl:ENSG00000182504
MYO5A GeneProduct ensembl:ENSG00000197535
RHOA GeneProduct ensembl:ENSG00000067560
MYO6 GeneProduct ensembl:ENSG00000196586
ARR3 GeneProduct ensembl:ENSG00000120500
FLNA GeneProduct ensembl:ENSG00000196924
PIBF1 GeneProduct ensembl:ENSG00000083535
BBS4 GeneProduct ensembl:ENSG00000140463
TCTN3 GeneProduct ensembl:ENSG00000119977
ARL2 GeneProduct ensembl:ENSG00000213465
TMEM138 GeneProduct ensembl:ENSG00000149483
KAT5 GeneProduct ensembl:ENSG00000172977
PARP1 GeneProduct ensembl:ENSG00000143799
PCM1 GeneProduct ensembl:ENSG00000078674 Component of the centriolar satellite.
CEP120 GeneProduct ensembl:ENSG00000168944
RP2 GeneProduct ensembl:ENSG00000102218
PDE6B GeneProduct ensembl:ENSG00000133256
BBS9 GeneProduct ensembl:ENSG00000122507
ATM GeneProduct ensembl:ENSG00000149311
RHEB GeneProduct ensembl:ENSG00000106615
DVL1 GeneProduct ensembl:ENSG00000107404
BBS5 GeneProduct ensembl:ENSG00000163093
BBS7 GeneProduct ensembl:ENSG00000138686
UNC119 GeneProduct ensembl:ENSG00000109103
NPHP4 GeneProduct ensembl:ENSG00000131697
SHH GeneProduct ensembl:ENSG00000164690
TCTN1 GeneProduct ensembl:ENSG00000204852
CPLANE1 GeneProduct ensembl:ENSG00000197603
ANKS6 GeneProduct ensembl:ENSG00000165138
NPHP3 GeneProduct ensembl:ENSG00000113971
MTOR GeneProduct ensembl:ENSG00000198793
TTC8 GeneProduct ensembl:ENSG00000165533
CSPP1 GeneProduct ensembl:ENSG00000104218
TMEM231 GeneProduct ensembl:ENSG00000205084
ARMC9 GeneProduct ensembl:ENSG00000135931
ARL13B GeneProduct ensembl:ENSG00000169379
INVS GeneProduct ensembl:ENSG00000119509
CCP110 GeneProduct ensembl:ENSG00000103540
CEP104 GeneProduct ensembl:ENSG00000116198
PDE6A GeneProduct ensembl:ENSG00000132915
ZNF423 GeneProduct ensembl:ENSG00000102935
NEK8 GeneProduct ensembl:ENSG00000160602
BBS1 GeneProduct ensembl:ENSG00000174483
TMEM237 GeneProduct ensembl:ENSG00000155755
MRE11 GeneProduct ensembl:ENSG00000020922
BBS2 GeneProduct ensembl:ENSG00000125124
PDE6G GeneProduct ensembl:ENSG00000185527
TCTN2 GeneProduct ensembl:ENSG00000168778
B9D1 GeneProduct ensembl:ENSG00000108641
RAD50 GeneProduct ensembl:ENSG00000113522
OFD1 GeneProduct ensembl:ENSG00000046651 Component of the centriolar satellite.
INPP5E GeneProduct ensembl:ENSG00000148384
CEP41 GeneProduct ensembl:ENSG00000106477
NPHP1 GeneProduct ensembl:ENSG00000144061
AHI1 GeneProduct ensembl:ENSG00000135541
INPP5E GeneProduct ensembl:ENSG00000148384
PDE6D GeneProduct ensembl:ENSG00000156973
ARL13B GeneProduct ensembl:ENSG00000169379
B9D2 GeneProduct ensembl:ENSG00000123810
CC2D2A GeneProduct ensembl:ENSG00000048342
MKS1 GeneProduct ensembl:ENSG00000011143
PDE6D GeneProduct ensembl:ENSG00000156973
RHEB GeneProduct ensembl:ENSG00000106615
PDE6D GeneProduct ensembl:ENSG00000156973
ARL3 GeneProduct ensembl:ENSG00000138175
UNC119 GeneProduct ensembl:ENSG00000109103
ZNF423 GeneProduct ensembl:ENSG00000102935
PDE6D GeneProduct ensembl:ENSG00000156973
RAB8A GeneProduct ensembl:ENSG00000167461
CEP290 GeneProduct ensembl:ENSG00000198707 Component of the centriolar satellite.
CEP164 GeneProduct ensembl:ENSG00000110274
DVL1 GeneProduct ensembl:ENSG00000107404
CEP290 GeneProduct ensembl:ENSG00000198707
ARL3 GeneProduct ensembl:ENSG00000138175
CEP164 GeneProduct ensembl:ENSG00000110274
OFD1 GeneProduct ensembl:ENSG00000046651
RAB8A GeneProduct ensembl:ENSG00000167461
RPGRIP1L GeneProduct ensembl:ENSG00000103494
PCNT Protein uniprot:O95613
NIN Protein uniprot:C9J066
CETN1 Protein uniprot:Q12798
CETN2 Protein uniprot:P41208

References

  1. Solubilization of membrane-bound rod phosphodiesterase by the rod phosphodiesterase recombinant delta subunit. Florio SK, Prusti RK, Beavo JA. J Biol Chem. 1996 Sep 27;271(39):24036–47. PubMed Europe PMC Scholia
  2. The isolation and characterization of a cDNA encoding phospholipid-specific inositol polyphosphate 5-phosphatase. Kisseleva MV, Wilson MP, Majerus PW. J Biol Chem. 2000 Jun 30;275(26):20110–6. PubMed Europe PMC Scholia
  3. Cloning and characterization of a 72-kDa inositol-polyphosphate 5-phosphatase localized to the Golgi network. Kong AM, Speed CJ, O’Malley CJ, Layton MJ, Meehan T, Loveland KL, et al. J Biol Chem. 2000 Aug 4;275(31):24052–64. PubMed Europe PMC Scholia
  4. Assembly of centrosomal proteins and microtubule organization depends on PCM-1. Dammermann A, Merdes A. J Cell Biol. 2002 Oct 28;159(2):255–66. PubMed Europe PMC Scholia
  5. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Kim JC, Badano JL, Sibold S, Esmail MA, Hill J, Hoskins BE, et al. Nat Genet. 2004 May;36(5):462–70. PubMed Europe PMC Scholia
  6. Characteristics of photoreceptor PDE (PDE6): similarities and differences to PDE5. Cote RH. Int J Impot Res. 2004 Jun;16 Suppl 1:S28-33. PubMed Europe PMC Scholia
  7. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Sayer JA, Otto EA, O’Toole JF, Nurnberg G, Kennedy MA, Becker C, et al. Nat Genet. 2006 Jun;38(6):674–81. PubMed Europe PMC Scholia
  8. CP110 cooperates with two calcium-binding proteins to regulate cytokinesis and genome stability. Tsang WY, Spektor A, Luciano DJ, Indjeian VB, Chen Z, Salisbury JL, et al. Mol Biol Cell. 2006 Aug;17(8):3423–34. PubMed Europe PMC Scholia
  9. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peränen J, Merdes A, et al. Cell. 2007 Jun 15;129(6):1201–13. PubMed Europe PMC Scholia
  10. Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Bergmann C, Fliegauf M, Brüchle NO, Frank V, Olbrich H, Kirschner J, et al. Am J Hum Genet. 2008 Apr;82(4):959–70. PubMed Europe PMC Scholia
  11. The retinitis pigmentosa 2 gene product is a GTPase-activating protein for Arf-like 3. Veltel S, Gasper R, Eisenacher E, Wittinghofer A. Nat Struct Mol Biol. 2008 Apr;15(4):373–80. PubMed Europe PMC Scholia
  12. Characterization of the Rheb-mTOR signaling pathway in mammalian cells: constitutive active mutants of Rheb and mTOR. Sato T, Umetsu A, Tamanoi F. Methods Enzymol. 2008;438:307–20. PubMed Europe PMC Scholia
  13. CP110 suppresses primary cilia formation through its interaction with CEP290, a protein deficient in human ciliary disease. Tsang WY, Bossard C, Khanna H, Peränen J, Swaroop A, Malhotra V, et al. Dev Cell. 2008 Aug;15(2):187–97. PubMed Europe PMC Scholia
  14. CEP290 interacts with the centriolar satellite component PCM-1 and is required for Rab8 localization to the primary cilium. Kim J, Krishnaswami SR, Gleeson JG. Hum Mol Genet. 2008 Dec 1;17(23):3796–805. PubMed Europe PMC Scholia
  15. CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Gorden NT, Arts HH, Parisi MA, Coene KLM, Letteboer SJF, van Beersum SEC, et al. Am J Hum Genet. 2008 Nov;83(5):559–71. PubMed Europe PMC Scholia
  16. Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking. Hsiao YC, Tong ZJ, Westfall JE, Ault JG, Page-McCaw PS, Ferland RJ. Hum Mol Genet. 2009 Oct 15;18(20):3926–41. PubMed Europe PMC Scholia
  17. Deciphering the structure and function of Als2cr4 in the mouse retina. Zuniga FI, Craft CM. Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4407–15. PubMed Europe PMC Scholia
  18. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, et al. Nat Genet. 2010 Jul;42(7):619–25. PubMed Europe PMC Scholia
  19. Centriolar satellites are assembly points for proteins implicated in human ciliopathies, including oral-facial-digital syndrome 1. Lopes CAM, Prosser SL, Romio L, Hirst RA, O’Callaghan C, Woolf AS, et al. J Cell Sci. 2011 Feb 15;124(Pt 4):600–12. PubMed Europe PMC Scholia
  20. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, et al. J Cell Biol. 2011 Mar 21;192(6):1023–41. PubMed Europe PMC Scholia
  21. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, et al. Nat Genet. 2011 Jul 3;43(8):776–84. PubMed Europe PMC Scholia
  22. Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo. Ismail SA, Chen YX, Rusinova A, Chandra A, Bierbaum M, Gremer L, et al. Nat Chem Biol. 2011 Oct 16;7(12):942–9. PubMed Europe PMC Scholia
  23. A meckelin-filamin A interaction mediates ciliogenesis. Adams M, Simms RJ, Abdelhamed Z, Dawe HR, Szymanska K, Logan CV, et al. Hum Mol Genet. 2012 Mar 15;21(6):1272–86. PubMed Europe PMC Scholia
  24. TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Huang L, Szymanska K, Jensen VL, Janecke AR, Innes AM, Davis EE, et al. Am J Hum Genet. 2011 Dec 9;89(6):713–30. PubMed Europe PMC Scholia
  25. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, et al. Cell. 2012 Aug 3;150(3):533–48. PubMed Europe PMC Scholia
  26. ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Humbert MC, Weihbrecht K, Searby CC, Li Y, Pope RM, Sheffield VC, et al. Proc Natl Acad Sci U S A. 2012 Nov 27;109(48):19691–6. PubMed Europe PMC Scholia
  27. The Joubert syndrome-associated missense mutation (V443D) in the Abelson-helper integration site 1 (AHI1) protein alters its localization and protein-protein interactions. Tuz K, Hsiao YC, Juárez O, Shi B, Harmon EY, Phelps IG, et al. J Biol Chem. 2013 May 10;288(19):13676–94. PubMed Europe PMC Scholia
  28. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Hoff S, Halbritter J, Epting D, Frank V, Nguyen TMT, van Reeuwijk J, et al. Nat Genet. 2013 Aug;45(8):951–6. PubMed Europe PMC Scholia
  29. Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling. Garcia-Gonzalo FR, Phua SC, Roberson EC, Garcia G 3rd, Abedin M, Schurmans S, et al. Dev Cell. 2015 Aug 24;34(4):400–9. PubMed Europe PMC Scholia
  30. MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone. Li C, Jensen VL, Park K, Kennedy J, Garcia-Gonzalo FR, Romani M, et al. PLoS Biol. 2016 Mar 16;14(3):e1002416. PubMed Europe PMC Scholia
  31. Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse. Wang C, Li J, Meng Q, Wang B. Dev Biol. 2017 Oct 1;430(1):156–65. PubMed Europe PMC Scholia
  32. Guanine nucleotide exchange factors activate Rab8a for Toll-like receptor signalling. Tong SJ, Wall AA, Hung Y, Luo L, Stow JL. Small GTPases. 2021 Jan;12(1):27–43. PubMed Europe PMC Scholia