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MKS1 regulates ciliary INPP5E levels in Joubert syndrome
  1. Gisela G Slaats1,
  2. Christine R Isabella2,
  3. Hester Y Kroes3,
  4. Jennifer C Dempsey2,
  5. Hendrik Gremmels1,
  6. Glen R Monroe3,
  7. Ian G Phelps2,
  8. Karen J Duran3,
  9. Jonathan Adkins2,4,
  10. Sairam A Kumar2,
  11. Dana M Knutzen2,
  12. Nine V Knoers3,
  13. Nancy J Mendelsohn5,
  14. David Neubauer6,
  15. Sotiria D Mastroyianni7,
  16. Julie Vogt8,
  17. Lisa Worgan9,
  18. Natalya Karp10,
  19. Sarah Bowdin11,
  20. Ian A Glass2,
  21. Melissa A Parisi12,
  22. Edgar A Otto13,
  23. Colin A Johnson14,
  24. Friedhelm Hildebrandt15,16,
  25. Gijs van Haaften3,
  26. Rachel H Giles1,
  27. Dan Doherty2,17
  1. 1Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Department of Pediatrics, University of Washington, Seattle, Washington, USA
  3. 3Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  4. 4Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona, USA
  5. 5Department of Medical Genetics, Children's Hospitals & Clinics of Minnesota, Minneapolis, Minnesota, USA
  6. 6Department of Child, Adolescent and Developmental Neurology, University Children's Hospital Ljubljana, Ljubljana, Slovenia
  7. 7Department of Neurology, Children's Hospital of Athens “P. and A. Kyriakou”, Athens, Greece
  8. 8West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, UK
  9. 9Department of Clinical Genetics, Liverpool Hospital, Liverpool, Australia
  10. 10Medical Genetics Program, Department of Pediatrics, London Health Science Centre, University of Western Ontario, London, Ontario, Canada
  11. 11Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
  12. 12Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
  13. 13Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA
  14. 14Section of Ophthalmology and Neuroscience, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, UK
  15. 15Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts, USA
  16. 16Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
  17. 17Seattle Children's Research Institute, Seattle, Washington, USA
  1. Correspondence to Dr Rachel H Giles, Department of Nephrology, F03.233, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands; r.giles{at}


Background Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation ‘the molar tooth sign’. Mutations in >27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1-related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS.

Methods We measured cilium number, length and protein content (ARL13B and INPP5E) by immunofluorescence in fibroblasts from individuals with MKS1-related JS and in a three-dimensional (3D) spheroid rescue assay to test the effects of disease-related MKS1 mutations.

Results We report MKS1 mutations (eight of them previously unreported) in nine individuals with JS. A minority of the individuals with MKS1-related JS have MKS features. In contrast to the truncating mutations associated with MKS, all of the individuals with MKS1-related JS carry ≥1 non-truncating mutation. Fibroblasts from individuals with MKS1-related JS make normal or fewer cilia than control fibroblasts, their cilia are more variable in length than controls, and show decreased ciliary ARL13B and INPP5E. Additionally, MKS1 mutant alleles have similar effects in 3D spheroids.

Conclusions MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content, through an ARL13B-dependent mechanism. Mutations in INPP5E also cause JS, so our findings in patient fibroblasts support the notion that loss of INPP5E function, due to either mutation or mislocalisation, is a key mechanism underlying JS, downstream of MKS1 and ARL13B.

  • Genetics
  • Cell biology

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