Identification of Genetic Suppressors of C. Elegans Fer-1
C. elegans fer-1 is the ancestral homolog of human Dysferlin. Mutations in fer-1 are known to cause infertility in C. elegans. Since genetic modifiers of LGMD2B/MM are known to exist, it is possible that homologous modifiers may also exist in other organisms such as C. elegans. Based on this rationale, we performed a large-scale mutagenic screen and isolated a number of genetic suppressor mutants that restore fertility to C. elegans carrying fer-1(hc1), a temperature-sensitive missense mutation in the FER-1 C2C domain. Thus far, we have identified four unique intragenic missense mutations in various C2 domains, which are capable of suppressing fer-1(hc1). We have also identified a dominant extragenic suppressor mutation, which we are currently mapping using a combined SNP detection / genome-wide sequencing approach.
In addition, we are testing previously isolated chemical suppressor of fer-1(hc1) in order to determine if any are capable of suppressing the fertility defect of the loss-of-function allele, fer-1(ok580). We will also perform a small molecule screen using a diverse compound library to identify novel compounds that are capable of suppressing the fertility defect of fer-1(ok580) animals.
The aim of this project is to characterize and genetically map the chromosomal location of a fer-1 loss-of-function suppressing mutation and to identify chemical suppressors capable of suppressing the loss of function allele fer-1(ok580).
Obtaining this information is the first step to identifying potential new therapeutic targets for the treatment of LGMD2B/MM and is likely to help identify constituents of biological pathways relevant to Dysferlin function.