Olson Bryan D, Sgourdou Paraskevi, Downes Gerald B
Genesis. 2010 Jun;48(6):354-61. doi: 10.1002/dvg.20631.
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.
斑马鱼胚胎表现出强劲的游泳行为，这种行为由平滑、交替的身体弯曲组成。相比之下，已经鉴定出几种运动突变体，它们会进行持续的双侧躯干肌肉收缩，导致身体异常缩短。与这些突变体中的大多数不同，手风琴（acc）（dta5）表现出半显性效应：杂合子表现出与纯合子不同但不太严重的表型。通过分子遗传图谱和候选基因分析，我们确定acc（dta5）突变体在atp2a1中存在一个新突变，该基因编码SERCA1，一种对肌肉松弛很重要的钙泵。先前的研究表明，其他八个acc等位基因损害了SERCA1的功能，但据报道这些等位基因都是隐性的。定量行为分析、互补测试和分子模型分析均表明，acc（dta5）突变通过单倍体不足或显性负性分子机制，比其他acc等位基因更大程度地降低了SERCA1的功能。由于人类ATP2A1的突变会导致布罗迪病，一种运动诱导的肌肉松弛障碍，acc（dta5）突变体可能为这种疾病提供一个特别敏感的模型。
