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

Disease Models & Mechanisms
Kristin M AtesYuchin Pan

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 d...Continue Reading

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Datasets Mentioned

BETA
GSE142673

Methods Mentioned

BETA
PCR
light microscopy
transgenic
RAP
immunoprecipitation

Key Resources (RRID) Mentioned

Addgene_22207

Software Mentioned

Fiji
Ensemble
BLAT
UCSC genome browser
Polyphen
Vector NTI
Photoshop
HTSeq
MEGA X
BLAST

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