Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development.

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of , the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 , utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, and , disrupted endocytosis and ciliogenesis in renal tissues. In addition, mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the double mutants. The abnormal renal and craniofacial phenotypes in the mutant animals were consistent with the clinical presentation of a patient with a arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient.This article has an associated First Person interview with the first author of the paper.