MKS1 regulates ciliary INPP5E levels in Joubert syndrome

Ciliopathies are disorders unified by shared pathophysiology and overlapping clinical phenotypes. MKS1 localizes to the base of the cilium, and MKS1 mutations are a major cause of the severe ciliopathy Meckel syndrome. We identified MKS1 mutations in nine families with the milder Joubert syndrome (JS), confirming a prior report linking MKS1 to JS. We demonstrate that JS-associated MKS1 mutations do not consistently alter cilium number or length, but they do reduce ciliary localization of ARL13B and consequently INPP5E. Given that INPP5E mutations also cause JS, we propose that INPP5E dysfunction is a central mechanism underlying JS, providing a pharmacologic target for future treatments. (By Gisela Slaats, http://jmg.bmj.com/content/early/2015/10/21/jmedgenet-2015-103250 )

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