Targeting impaired autophagy as a therapeutic strategy for Koolen-de Vries syndrome.

Koolen-de Vries syndrome (KdVS) is a genomic disorder characterized by intellectual disability, heart failure, hypotonia and congenital malformations, which is caused by haploinsufficiency of KANSL1. Because the pathogenesis of the disease is unknown, there is still no effective treatment. Here, we discuss our recent work identifying KANSL1 as an essential gene for macroautophagy/autophagy. We find that KANSL1 modulates autophagosome-lysosome fusion for cargo degradation by transcriptionally regulating Stx17 expression. Kansl1 heterozygous mice exhibit impaired neuronal and cardiac functions, resulting from the obstruction of autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species in these tissues. Furthermore, we discovered an FDA-approved drug, 13-cis retinoic acid, is capable of alleviating these mitophagic defects and neurobehavioral abnormalities in Kansl1 heterozygous mice by promoting autophagosome-lysosome fusion via directly binding to STX17 and SNAP29. Our study provides the proof of concept to set up a link between KANSL1, autophagic defects and KdVS, and also proposes a therapeutic strategy for treatment of KdVS.