A novel early onset phenotype in a zebrafish model of merosin deficient congenital muscular dystrophy

Merosin deficient congenital muscular dystrophy (MDC1A) is a severe neuromuscular disorder with onset in infancy that is associated with severe morbidities (particularly wheelchair dependence) and early mortality. It is caused by recessive mutations in the LAMA2 gene that encodes a subunit of the extracellular matrix protein laminin 211. At present, there are no treatments for this disabling disease. The zebrafish has emerged as a powerful model system for the identification of novel therapies. However, drug discovery in the zebrafish is largely dependent on the identification of phenotypes suitable for chemical screening. Our goal in this study was to elucidate novel, early onset abnormalities in the candyfloss (caf) zebrafish, a model of MDC1A. We uncovered and characterize abnormalities in spontaneous coiling, the earliest motor movement in the zebrafish, as a fully penetrant change specific to caf mutants that is ideal for future drug testing.

层粘连蛋白缺乏型先天性肌营养不良（Merosin deficient congenital muscular dystrophy, MDC1A）是一种起病于婴儿期的重型神经肌肉疾病，常伴随严重并发症（尤以需依赖轮椅为典型表现）及早期死亡风险。该病由编码细胞外基质蛋白层粘连蛋白211（laminin 211）亚基的LAMA2基因发生隐性突变所致。目前，针对这一致残性疾病尚无有效治疗方案。斑马鱼（zebrafish）已成为筛选新型治疗手段的高效模型系统，但斑马鱼模型的药物研发高度依赖适用于化学筛选的表型鉴定。本研究以MDC1A疾病模型candyfloss（caf）斑马鱼为对象，旨在阐明其新型早发性异常。我们发现并表征了自发性卷曲运动（spontaneous coiling）的异常：这是斑马鱼最早出现的运动行为，该异常在caf突变体中呈现完全外显的特异性改变，非常适合用于后续药物测试。