Loss ofcped1does not affect bone and lean mass in zebrafish

Abstract

Human genetic studies have nominated Cadherin-like and PC-esterase Domain-containing 1 (CPED1) as a candidate target gene mediating bone mineral density (BMD) and fracture risk heritability. Recent efforts to define the role ofCPED1in bone in mouse and human models have revealed complex alternative splicing and inconsistent results arising from gene targeting, making its function difficult to interpret. To better understand the role ofCPED1in adult bone mass and morphology, we turned to zebrafish, an emerging model for orthopaedic research. We analyzed two differentcped1mutant lines and performed deep phenotyping to characterize more than 200 measures of adult vertebral, craniofacial, and lean tissue morphology. We also examined alternative splicing of zebrafishcped1and gene expression in various cell/tissue types. Our studies fail to support an essential role ofcped1in adult zebrafish bone. Specifically, homozygous mutants for bothcped1mutant alleles, which are expected to result in loss-of-function and impact allcped1isoforms, exhibited no significant differences in the measures examined when compared to their respective wildtype controls, suggesting thatcped1does not significantly contribute to these traits. We identified sequence differences in critical residues of the catalytic triad between the zebrafish and mouse orthologs of CPED1, and discuss how these differences, as well as distinct alternative splicing, could underlie different functions ofCPED1orthologs in the two species. Our studies demonstrate thatcped1is not required for normal adult zebrafish bone mass, lean mass, or bone and lean mass morphology, adding to evidence that variants at 7q31.31 can act independently ofCPED1to influence BMD and fracture risk.