ALMS1 stabilizes the proximal centriole to drive transition zone assembly and ciliogenesis

The human ciliopathy Alström syndrome is caused by mutations in ALMS1. How ALMS1 contributes to cilia function has been unclear. Unlike other ciliopathy-associated proteins, ALMS1 localizes to the proximal end of centrioles, raising the possibility that it contributes to cilia function via a distinct mechanism. We found that, without ALMS1, centrioles are short and frequently break at their proximal ends. Truncated, broken ALMS1 mutant centrioles display reduced microtubule-organizing activity and disrupted centriole linkers. Without ALMS1, Golgi-derived cargos, including transmembrane components of the transition zone, are impaired in their trafficking to the centrosome. Consequently, ALMS1 is important for transition zone assembly, ciliogenesis, and the control of ciliary membrane composition. In mice, disruption of ALMS1 causes progressive, age-dependent loss of cilia in tissues affected in Alström syndrome, including retina, kidney, and brain. We conclude that Alström syndrome is caused by disruption of proximal centriole integrity and centrosome-directed protein trafficking, compromising ciliary assembly and maintenance.