ZFIN ID: ZDB-PUB-200403-16
Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development
Ates, K.M., Wang, T., Moreland, T., Veeranan-Karmegam, R., Ma, M., Jeter, C., Anand, P., Wenzel, W., Kim, H.G., Wolfe, L.A., Stephen, J.A., Adams, D.R., Markello, T., Tifft, C.J., Settlage, R., Gahl, W.A., Gonsalvez, G.B., Malicdan, M.C., Flanagan-Steet, H., Pan, Y.A.
Date: 2020
Source: Disease models & mechanisms   13(5): (Journal)
Registered Authors: Flanagan-Steet, Heather, Jeter, Chelsi, Pan, Y. Albert, Wang, Tong
Keywords: Endocytosis, IPIP27A, OCRL, PHETA1, Undiagnosed disease
Microarrays: GEO:GSE142673
MeSH Terms:
  • Adaptor Proteins, Signal Transducing/chemistry
  • Adaptor Proteins, Signal Transducing/deficiency*
  • Adaptor Proteins, Signal Transducing/metabolism
  • Amino Acid Sequence
  • Animals
  • CRISPR-Cas Systems/genetics
  • Cathepsin K/metabolism
  • Cell Differentiation
  • Chondrocytes/pathology
  • Cilia/pathology
  • Collagen Type II/metabolism
  • Endocytosis*
  • Face/embryology*
  • Genes, Dominant
  • HeLa Cells
  • Humans
  • Kidney/embryology*
  • Morphogenesis
  • Motor Activity
  • Mutation/genetics
  • Pronephros/pathology
  • Skull/embryology*
  • Undiagnosed Diseases/diagnostic imaging
  • Undiagnosed Diseases/genetics
  • Vesicular Transport Proteins/chemistry
  • Vesicular Transport Proteins/genetics
  • Zebrafish
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/deficiency*
  • Zebrafish Proteins/metabolism
PubMed: 32152089 Full text @ Dis. Model. Mech.
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 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.