TY - JOUR
T1 - Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development
AU - Ates, Kristin M.
AU - Wang, Tong
AU - Moreland, Trevor
AU - Veeranan-Karmegam, Rajalakshmi
AU - Ma, Manxiu
AU - Jeter, Chelsi
AU - Anand, Priya
AU - Wenzel, Wolfgang
AU - Kim, Hyung Goo
AU - Wolfe, Lynne A.
AU - Stephen, Joshi
AU - Adams, David R.
AU - Markello, Thomas
AU - Tifft, Cynthia J.
AU - Settlage, Robert
AU - Gahl, William A.
AU - Gonsalvez, Graydon B.
AU - Malicdan, May Christine
AU - Flanagan-Steet, Heather
AU - Albert Pan, Y.
N1 - Publisher Copyright:
© 2020. Published by The Company of Biologists Ltd
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
KW - Endocytosis
KW - IPIP27A
KW - OCRL
KW - PHETA1
KW - Undiagnosed disease
UR - http://www.scopus.com/inward/record.url?scp=85085534663&partnerID=8YFLogxK
U2 - 10.1242/dmm.041913
DO - 10.1242/dmm.041913
M3 - Article
C2 - 32152089
AN - SCOPUS:85085534663
SN - 1754-8403
VL - 13
JO - DMM Disease Models and Mechanisms
JF - DMM Disease Models and Mechanisms
IS - 5
M1 - dmm041913
ER -