Disease Models & Mechanisms
| العنوان: | Disease Models & Mechanisms |
|---|---|
| المؤلفون: | Rajalakshmi Veeranan-Karmegam, Priya Anand, Manxiu Ma, Graydon B. Gonsalvez, Trevor Moreland, Kristin M. Ates, Chelsi Jeter, Cynthia J. Tifft, Wolfgang Wenzel, Robert E. Settlage, William A. Gahl, David R. Adams, Tong Wang, May Christine V. Malicdan, Lynne A. Wolfe, Hyung-Goo Kim, Heather Flanagan-Steet, Thomas C. Markello, Joshi Stephen, Y. Albert Pan |
| المساهمون: | Fralin Biomedical Research Institute, Virginia Tech Carilion School of Medicine, Biomedical Sciences and Pathobiology, Advanced Research Computing |
| المصدر: | Disease Models & Mechanisms, Vol 13, Iss 5 (2020) Disease Models & Mechanisms article-version (VoR) Version of Record Disease models & mechanisms, 13 (5), Art. Nr.: dmm041913 |
| بيانات النشر: | The Company of Biologists, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Technology, IPIP27A, Endocytic cycle, Cathepsin K, Vesicular Transport Proteins, Medicine (miscellaneous), lcsh:Medicine, Kidney, Immunology and Microbiology (miscellaneous), Morphogenesis, Zebrafish, Genes, Dominant, ipip27a, biology, Signal transducing adaptor protein, Cell Differentiation, Endocytosis, Cell biology, PHETA1, Research Article, lcsh:RB1-214, Endosome, Neuroscience (miscellaneous), Motor Activity, Undiagnosed Diseases, General Biochemistry, Genetics and Molecular Biology, Pronephros, Chondrocytes, ocrl, Ciliogenesis, lcsh:Pathology, Animals, Humans, endocytosis, Amino Acid Sequence, Cilia, Craniofacial, Collagen Type II, Adaptor Proteins, Signal Transducing, OCRL, Skull, undiagnosed disease, lcsh:R, Zebrafish Proteins, biology.organism_classification, Zebra, Face, Mutation, Undiagnosed disease, CRISPR-Cas Systems, ddc:600, HeLa Cells, pheta1 |
| الوصف: | 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. 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. Editor's choice: The functions of two endocytic adaptor proteins, PHETA1/2, are determined using zebrafish mutants and a potentially disease-causing variant of human PHETA1. Findings suggest essential roles in craniofacial and renal development. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1754-8411 1754-8403 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::99b87236f37ef87b91e3e07183d08d4aTest http://dmm.biologists.org/content/13/5/dmm041913Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....99b87236f37ef87b91e3e07183d08d4a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17548411 17548403 |
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