Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Dis Model Mech ; 13(5)2020 05 26.
Article in English | MEDLINE | ID: mdl-32152089

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 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.


Subject(s)
Adaptor Proteins, Signal Transducing/deficiency , Endocytosis , Face/embryology , Kidney/embryology , Skull/embryology , Zebrafish Proteins/deficiency , Adaptor Proteins, Signal Transducing/chemistry , 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 , Genes, Dominant , HeLa Cells , Humans , Morphogenesis , Motor Activity , Mutation/genetics , Pronephros/pathology , Undiagnosed Diseases/diagnostic imaging , Undiagnosed Diseases/genetics , Vesicular Transport Proteins/chemistry , Vesicular Transport Proteins/genetics , Zebrafish , Zebrafish Proteins/chemistry , Zebrafish Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...