J Pediatr Genet 2014; 03(02): 065-078
DOI: 10.3233/PGE-14090
Review Article
Georg Thieme Verlag KG Stuttgart – New York

Unraveling the genetics of Joubert and Meckel-Gruber syndromes

Katarzyna Szymanska
a  Department of Ophthalmology and Neuroscience, University of Leeds, Leeds, UK
Verity L. Hartill
a  Department of Ophthalmology and Neuroscience, University of Leeds, Leeds, UK
Colin A. Johnson
a  Department of Ophthalmology and Neuroscience, University of Leeds, Leeds, UK
› Author Affiliations

Subject Editor:
Further Information

Publication History

27 May 2014

14 July 2014

Publication Date:
27 July 2015 (online)


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.