Conference Paper
Homocystinuria in Cavefish: Molecular analysis of an Astyanax eye QTL reveals the role of cystathionine ß-synthase in eye degeneration
Jeffery, W.R.
Record Number:
3895
Year:
2016
Abstract:
Cavefish eye degeneration is a multigenic trait represented by quantitative trait loci (QTL) spread throughout the Astyanax genome. The identity of the responsible genes within the eye QTL, the nature of the underlying mutations, and the roles they play in eye development and degeneration are unknown. We identify here a mutated gene in a QTL on Astyanax chromosome 21 that is involved in cavefish eye degeneration. According to the draft cavefish genome sequence, the chromosome 21 QTL contains 24 protein-coding genes. We found that 21 of these genes are expressed during the critical period of cavefish eye degeneration: 15 genes showed no change, 3 genes were upregulated, and 3 genes were downregulated in surface fish relative to cavefish embryos. Analysis of gene expression in F1 hybrids suggested that one of the downregulated genes, cystathionine ß-synthase a (cbsa), harbors a cis-acting mutation. Based on genome wide ATAC sequencing and open chromatin analysis, a putative enhancer in a large cbsa intron is a strong candidate for this mutation. The cbsa gene, which is expressed at high levels in the lens and optic cup in surface fish but not cavefish embryos, encodes the CBS enzyme that is responsible for conversion of homocysteine to cysteine in the transsulfuration pathway producing glutathione, the major antioxidant in the eye. Human CBS mutations result in toxic homocysteine accumulation and lead to homocystinuria, a hereditary disease with debilitating effects on the eye. Similarly in Astyanax, knockdown of the surface fish cbsa gene caused defects in eye development, and ELISA showed that homocysteine is elevated in cavefish embryos during the critical period of eye degeneration. The results suggest that the cavefish regressive eye phenotype resembles CBS-related homocystinuria and may be caused in part by breakdown of the defense system protecting the eye against chemical and oxidative stress.
Times Cited:
1
Conference Name:
23rd International Conference on Subterranean Biology
Conference Year:
2016
Conference Location:
2016
Conference Location:
2016
Relevent Species: