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

2020-05

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
Adams, David R.
Markello, Thomas
Tifft, Cynthia J.
Settlage, Robert E.
Gahl, William A.
Gonsalvez, Graydon B.
Malicdan, May Christine
Flanagan-Steet, Heather
Pan, Yuchin Albert

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, phetal 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 presentation 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. This article has an associated First Person interview with the first author of the paper.

PHETA1; IPIP27A; OCRL; Endocytosis; Undiagnosed disease; Article - Refereed

10.1242.dmm.041913

Open access content. Open access content
Creative Commons Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0

English

VPI oai:vtechworks.lib.vt.edu:10919/99804
doi:10.1242/dmm.041913
EISSN:1754-8411
ISSN:1754-8403
1357881201

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