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

• Published in: Disease models & mechanisms 2020-01
• Main Authors: Ates, Kristin M, Wang, Tong, Moreland, Trevor, Veeranan-Karmegam, Rajalakshmi, Ma, Manxiu, Jeter, Chelsi, Anand, Priya, Wenzel, Wolfgang, Kim, Hyung-Goo, Wolfe, Lynne A, Stephen, Joshi A, Adams, David R, Markello, Thomas, Tifft, Cynthia J, Settlage, Robert, Gahl, William A, Gonsalvez, Graydon B, Malicdan, May Christine, Flanagan-Steet, Heather, Pan, Y Albert
• Format: Article
• Language: English
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.041913

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo 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 OCRL, the causative gene for Lowe syndrome. Here we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 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 pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentations of a patient with a de novo 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 in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient.