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

Abstract

The functions of two endocytic adaptor proteins, PHETA1/2, are determined using zebrafish mutants and a potentially disease-causing variant of human PHETA1. Findings suggest essential roles in craniofacial and renal development.

Comprehensive Transcriptomic Profiling of Murine Osteoclast Differentiation Reveals Novel Differentially Expressed Genes and LncRNAs

“…The proteins encoded by these genes are primarily associated with biochemical or signaling pathways at the cellular level and defects in expression may lead to certain disorders. For instance, anomalies in PHETA1/2 have been associated with abnormal bone formation resulting in craniofacial defects ( Ates et al, 2020 ), HAGH has been associated with skin, bone and joint infections in Yaws disease ( Cheng et al, 2018 ) and mutations in GFPT1 have been associated with muscle weakness in congenital myasthenic syndrome ( Helman et al, 2019 ). In addition, histone-related genes H2B Clustered Histone 21 ( H2bc21 ) and H2bc4 were also significantly upregulated during osteoclast differentiation.…”

Craniofacial Diseases Caused by Defects in Intracellular Trafficking

“…PHETA1and 2 are also involved in the sorting of lysosomal hydrolases [ 38 ]. A patient with craniofacial dysmorphism was identified with a heterozygous de novo arginine to cysteine variant (R6C) in PHETA1 ( Table 1 ) [ 40 ]. As the variant did not affect its mRNA expression, the functional role of PHETA1 and PHETA2 was analyzed in zebrafish mutants.…”

“…pheta 2 knockout mutants showed more severe craniofacial phenotypes than pheta 1 knockout mutants. In pheta 1 knockout animals, Meckel’s area and the width and length of the jaw were reduced, but pheta 2 knockout animals were more severely affected in all parameters measured [ 40 ]. Interestingly, the patient with the de novo heterozygous R6C variant in PHETA1 had a significantly reduced jaw width [ 40 ].…”

“…In pheta 1 knockout animals, Meckel’s area and the width and length of the jaw were reduced, but pheta 2 knockout animals were more severely affected in all parameters measured [ 40 ]. Interestingly, the patient with the de novo heterozygous R6C variant in PHETA1 had a significantly reduced jaw width [ 40 ]. As PHETA1 and 2 can form both a homodimer and a heterodimer, it was suggested that the R6C variant acts on the craniofacial development in a dominant-negative manner.…”

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“…The proteins encoded by these genes are primarily associated with biochemical or signaling pathways at the cellular level and defects in expression may lead to certain disorders. For instance, anomalies in PHETA1/2 have been associated with abnormal bone formation resulting in craniofacial defects (Ates et al, 2020), HAGH has been associated with skin, bone and joint infections in Yaws disease (Cheng et al, 2018) and mutations in GFPT1 have been associated with muscle weakness in congenital myasthenic syndrome (Helman et al, 2019). In addition, histone-related genes H2B Clustered Histone 21 (H2bc21) and H2bc4 were also significantly upregulated during osteoclast differentiation.…”