2. Academic Validation
  3. MKS1 regulates ciliary INPP5E levels in Joubert syndrome

MKS1 regulates ciliary INPP5E levels in Joubert syndrome

  • J Med Genet. 2016 Jan;53(1):62-72. doi: 10.1136/jmedgenet-2015-103250.
Gisela G Slaats 1,  Christine R Isabella 2,  Hester Y Kroes 3,  Jennifer C Dempsey 2,  Hendrik Gremmels 1,  Glen R Monroe 3,  Ian G Phelps 2,  Karen J Duran 3,  Jonathan Adkins 4,  Sairam A Kumar 2,  Dana M Knutzen 2,  Nine V Knoers 3,  Nancy J Mendelsohn 5,  David Neubauer 6,  Sotiria D Mastroyianni 7,  Julie Vogt 8,  Lisa Worgan 9,  Natalya Karp 10,  Sarah Bowdin 11,  Ian A Glass 2,  Melissa A Parisi 12,  Edgar A Otto 13,  Colin A Johnson 14,  Friedhelm Hildebrandt 15,  Gijs van Haaften 3,  Rachel H Giles 1,  Dan Doherty 16
Affiliations

Affiliations

  • 1 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 2 Department of Pediatrics, University of Washington, Seattle, Washington, USA.
  • 3 Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 4 Department of Pediatrics, University of Washington, Seattle, Washington, USA Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona, USA.
  • 5 Department of Medical Genetics, Children's Hospitals & Clinics of Minnesota, Minneapolis, Minnesota, USA.
  • 6 Department of Child, Adolescent and Developmental Neurology, University Children's Hospital Ljubljana, Ljubljana, Slovenia.
  • 7 Department of Neurology, Children's Hospital of Athens "P. and A. Kyriakou", Athens, Greece.
  • 8 West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, UK.
  • 9 Department of Clinical Genetics, Liverpool Hospital, Liverpool, Australia.
  • 10 Medical Genetics Program, Department of Pediatrics, London Health Science Centre, University of Western Ontario, London, Ontario, Canada.
  • 11 Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 12 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
  • 13 Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
  • 14 Section of Ophthalmology and Neuroscience, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, UK.
  • 15 Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
  • 16 Department of Pediatrics, University of Washington, Seattle, Washington, USA Seattle Children's Research Institute, Seattle, Washington, USA.
PMID: 26490104 DOI: 10.1136/jmedgenet-2015-103250
Abstract

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.

Keywords

Cell biology; Genetics.

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