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

Ates, K. M.; Wang, T.; Moreland, T.; Veeranan-Karmegam, R.; Ma, M.; Jeter, C.; Anand, P. 1; Wenzel, W. 1; Kim, H.-G.; Wolfe, L. A.; Stephen, J.; Adams, D. R.; Markello, T.; Tifft, C. J.; Settlage, R.; Gahl, W. A.; Gonsalvez, G. B.; Malicdan, M. C.; Flanagan-Steet, H.; ... mehr


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 presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. ... mehr

Verlagsausgabe §
DOI: 10.5445/IR/1000120561
Veröffentlicht am 24.08.2020
DOI: 10.1242/dmm.041913
Zitationen: 5
Web of Science
Zitationen: 6
Zitationen: 8
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Nanotechnologie (INT)
Publikationstyp Zeitschriftenaufsatz
Publikationsmonat/-jahr 05.2020
Sprache Englisch
Identifikator ISSN: 1754-8403, 1754-8411
KITopen-ID: 1000120561
HGF-Programm 43.21.04 (POF III, LK 01) Molecular Engineering
Erschienen in Disease models & mechanisms
Verlag The Company of Biologists
Band 13
Heft 5
Seiten Art. Nr.: dmm041913
Schlagwörter PHETA1, IPIP27A, OCRL, Endocytosis, Undiagnosed disease
Nachgewiesen in Web of Science
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