Analysis of a zebrafish behavioral mutant reveals a dominant mutation in atp2a1/SERCA1

Abstract

Zebrafish embryos demonstrate robust swimming behavior, which consists of smooth, alternating body bends. In contrast, several motility mutants have been identified that perform sustained, bilateral trunk muscle contractions which result in abnormal body shortening. Unlike most of these mutants, accordion (acc)(dta5) demonstrates a semidominant effect: Heterozygotes exhibit a distinct but less severe phenotype than homozygotes. Using molecular-genetic mapping and candidate gene analysis, we determined that acc(dta5) mutants harbor a novel mutation in atp2a1, which encodes SERCA1, a calcium pump important for muscle relaxation. Previous studies have shown that eight other acc alleles compromise SERCA1 function, but these alleles were all reported to be recessive. Quantitative behavioral assays, complementation testing, and analysis of molecular models all indicate that the acc(dta5) mutation diminishes SERCA1 function to a greater degree than other acc alleles through either haploinsufficient or dominant-negative molecular mechanisms. Since mutation of human ATP2A1 results in Brody disease, an exercise-induced impairment of muscle relaxation, acc(dta5) mutants may provide a particularly sensitive model of this disorder.