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

Kristin M. Ates, Tong Wang, Trevor Moreland, Rajalakshmi Veeranan-Karmegam, Priya Anand, Wolfgang Wenzel, Hyung-Goo Kim, Lynne A. Wolfe, Joshi Stephen, David R. Adams, Thomas Markello, Cynthia J. Tifft, William A. Gahl, Graydon B. Gonsalvez, May Christine Malicdan, Heather Flanagan-Steet, Y. Albert Pan
doi: https://doi.org/10.1101/727578
Kristin M. Ates
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912Center for Neurobiology Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA 24016
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Tong Wang
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912Greenwood Genetic Center, Greenwood, SC 29646
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Trevor Moreland
Greenwood Genetic Center, Greenwood, SC 29646
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Rajalakshmi Veeranan-Karmegam
Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912
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Priya Anand
Institute of Nanotechnology, Karlsruhe Institute of Technology, Karlsruhe, Germany
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Wolfgang Wenzel
Institute of Nanotechnology, Karlsruhe Institute of Technology, Karlsruhe, Germany
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Hyung-Goo Kim
Neurological Disorder Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
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Lynne A. Wolfe
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892National Institute of Health Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892
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Joshi Stephen
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892National Institute of Health Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892
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David R. Adams
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892National Institute of Health Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892
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Thomas Markello
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892National Institute of Health Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892
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Cynthia J. Tifft
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892National Institute of Health Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892
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William A. Gahl
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892National Institute of Health Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892
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Graydon B. Gonsalvez
Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912
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May Christine Malicdan
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892National Institute of Health Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892
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Heather Flanagan-Steet
Greenwood Genetic Center, Greenwood, SC 29646
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Y. Albert Pan
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912Center for Neurobiology Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA 24016
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  • For correspondence: yapan@vtc.vt.edu
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Abstract

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 addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte maturation, 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. 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.

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Posted August 06, 2019.
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Deficiency in the endocytic adaptor protein PHETA1/2 impairs renal and craniofacial development
Kristin M. Ates, Tong Wang, Trevor Moreland, Rajalakshmi Veeranan-Karmegam, Priya Anand, Wolfgang Wenzel, Hyung-Goo Kim, Lynne A. Wolfe, Joshi Stephen, David R. Adams, Thomas Markello, Cynthia J. Tifft, William A. Gahl, Graydon B. Gonsalvez, May Christine Malicdan, Heather Flanagan-Steet, Y. Albert Pan
bioRxiv 727578; doi: https://doi.org/10.1101/727578
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Deficiency in the endocytic adaptor protein PHETA1/2 impairs renal and craniofacial development
Kristin M. Ates, Tong Wang, Trevor Moreland, Rajalakshmi Veeranan-Karmegam, Priya Anand, Wolfgang Wenzel, Hyung-Goo Kim, Lynne A. Wolfe, Joshi Stephen, David R. Adams, Thomas Markello, Cynthia J. Tifft, William A. Gahl, Graydon B. Gonsalvez, May Christine Malicdan, Heather Flanagan-Steet, Y. Albert Pan
bioRxiv 727578; doi: https://doi.org/10.1101/727578

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