Trafficking new GPCRs and regulators to primary cilia

摘要

Genetic heterogeneity mirrors the clinical heterogeneityof JSRD. Over 17 genes have been identified, all encodingfor proteins of the primary cilium, with intriguing allelicseries and clinical correlations that have made these conditionsa paradigmatic example of “splitting and lumping”in human genetics. Indeed, the same phenotype can becaused by mutations in distinct genes, and conversely thesame gene can be responsible of distinct ciliopathies,such as JSRD, nephronophthisis, Senior-Loken, Bardet-Biedl and Meckel syndromes. Of note, there is clinicalheterogeneity even within families, with affected siblingsdiscordant for features such as encephalocele or retinalinvolvement. This extreme phenotypic variability associatedwith mutations in one and the same gene remainsa main open question. An intriguing explanation hasimplicated an oligogenic model of inheritance (alreadydemonstrated for Bardet-Biedl syndrome and other ciliopathies),in which mutations, rare variants and even polymorphismsat distinct loci epistatically interplay tomodulate the ciliopathy phenotype. To date, mutationanalyses of most JSRD-causative genes have not beenperformed in large cohorts, and the systematic geneticscreening of multiple ciliopathy genes remains a stillunmet need to address the complexity of JSRD genetics.