Loss of <i>cped1</i> does not affect bone and lean tissue in zebrafish

Human genetic studies have nominated cadherin-like and PC-esterase domain-containing 1 (<i>CPED1</i>) as a candidate target gene mediating bone mineral density (BMD) and fracture risk heritability. Recent efforts to define the role of <i>CPED1</i> in bone in mouse and human models have revealed complex alternative splicing and inconsistent results arising from gene targeting, making its function in bone difficult to interpret. To better understand the role of <i>CPED1</i> in adult bone mass and morphology, we conducted a comprehensive genetic and phenotypic analysis of <i>cped1</i> in zebrafish, an emerging model for bone and mineral research. We analyzed two different <i>cped1</i> mutant 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 zebrafish <i>cped1</i> and gene expression in various cell/tissue types. Our studies fail to support an essential role of <i>cped1</i> in adult zebrafish bone. Specifically, homozygous mutants for both <i>cped1</i> mutant alleles, which are expected to result in loss-of-function and impact all <i>cped1</i> isoforms, exhibited no significant differences in the measures examined when compared to their respective wildtype controls, suggesting that <i>cped1</i> does 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, suggesting that differences in key residues, as well as distinct alternative splicing, could underlie different functions of CPED1 orthologs in the two species. Our studies fail to support a requirement of <i>cped1</i> in zebrafish bone and lean tissue, adding to evidence that variants at 7q31.31 can act independently of <i>CPED1</i> to influence BMD and fracture risk.