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Unraveling the genetics of Joubert and Meckel-Gruber syndromes

Issue title: Ciliopathies

Article type: Research Article

Authors: Szymanska, Katarzyna | Hartill, Verity L. | Johnson, Colin A.

Affiliations: Department of Ophthalmology and Neuroscience, University of Leeds, Leeds, UK

Note: [] Corresponding author: Colin A. Johnson, PhD, Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. Tel.: +44 (0) 113 343 8443; Fax: +44 (0) 113 343 8603; E-mail: [email protected]

Keywords: Joubert syndrome, Meckel-Gruber syndrome, primary cilium, transition zone

DOI: 10.3233/PGE-14090

Journal: Journal of Pediatric Genetics, vol. 3, no. 2, pp. 65-78, 2014

Received 27 May 2014
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Revision received 11 July 2014
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Accepted 14 July 2014
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Published: 2014
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Abstract

Joubert syndrome (JBTS) and Meckel-Gruber syndrome (MKS) are recessive neurodevelopmental conditions caused by mutations in proteins that are structural or functional components of the primary cilium. In this review, we provide an overview of their clinical diagnosis, management and molecular genetics. Both have variable phenotypes, extreme genetic heterogeneity, and display allelism both with each other and other ciliopathies. Recent advances in genetic technology have significantly improved diagnosis and clinical management of ciliopathy patients, with the delineation of some general genotype-phenotype correlations. We highlight those that are most relevant for clinical practice, including the correlation between TMEM67 mutations and the JBTS variant phenotype of COACH syndrome. The subcellular localization of the known MKS and JBTS proteins is now well-described, and we discuss some of the contemporary ideas about ciliopathy disease pathogenesis. Most JBTS and MKS proteins localize to a discrete ciliary compartment called the transition zone, and act as structural components of the so-called “ciliary gate” to regulate the ciliary trafficking of cargo proteins or lipids. Cargo proteins include enzymes and transmembrane proteins that mediate intracellular signaling. The disruption of transition zone function may contribute to the ciliopathy phenotype by altering the composition of the ciliary membrane or axoneme, with impacts on essential developmental signaling including the Wnt and Shh pathways as well as the regulation of secondary messengers such as inositol-1,4,5-trisphosphate (InsP3) and cyclic adenosine monophosphate (cAMP). However, challenges remain in the interpretation of the pathogenic potential of genetic variants of unknown significance, and in the elucidation of the molecular mechanisms of phenotypic variability in JBTS and MKS. The further genetic and functional characterization of these conditions is essential to prioritize patients for new targeted therapies.