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

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dc.contributor.authorAtes, Kristin M.en
dc.contributor.authorWang, Tongen
dc.contributor.authorMoreland, Trevoren
dc.contributor.authorVeeranan-Karmegam, Rajalakshmien
dc.contributor.authorMa, Manxiuen
dc.contributor.authorJeter, Chelsien
dc.contributor.authorAnand, Priyaen
dc.contributor.authorWenzel, Wolfgangen
dc.contributor.authorKim, Hyung-Gooen
dc.contributor.authorWolfe, Lynne A.en
dc.contributor.authorStephen, Joshien
dc.contributor.authorAdams, David R.en
dc.contributor.authorMarkello, Thomasen
dc.contributor.authorTifft, Cynthia J.en
dc.contributor.authorSettlage, Robert E.en
dc.contributor.authorGahl, William A.en
dc.contributor.authorGonsalvez, Graydon B.en
dc.contributor.authorMalicdan, May Christineen
dc.contributor.authorFlanagan-Steet, Heatheren
dc.contributor.authorPan, Yuchin Alberten
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentVirginia Tech Carilion School of Medicineen
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.contributor.departmentAdvanced Research Computingen
dc.date.accessioned2020-08-21T14:15:35Zen
dc.date.available2020-08-21T14:15:35Zen
dc.date.issued2020-05en
dc.description.abstractA 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.en
dc.description.notesThis work was supported by the National Institutes of Health (GM119016 to H.-G.K., G.B.G. and Y.A.P.; GM086524 to H.F.-S.), the Commonwealth Research Commercialization Fund (ER14S-001-LS to Y.A.P.), Augusta University, and Virginia Polytechnic Institute and State University.en
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [GM119016, GM086524]; Commonwealth Research Commercialization Fund [ER14S-001-LS]; Virginia Polytechnic Institute and State University; Augusta Universityen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1242/dmm.041913en
dc.identifier.eissn1754-8411en
dc.identifier.issn1754-8403en
dc.identifier.issue5en
dc.identifier.otherdmm041913en
dc.identifier.pmid32152089en
dc.identifier.urihttp://hdl.handle.net/10919/99804en
dc.identifier.volume13en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectPHETA1en
dc.subjectIPIP27Aen
dc.subjectOCRLen
dc.subjectEndocytosisen
dc.subjectUndiagnosed diseaseen
dc.titleDeficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial developmenten
dc.title.serialDisease Models & Mechanismsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen
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