Identification of Genetic Suppressors of C. Elegans Fer-1

Mohan Viswanathan, PhD

Massachusetts Institute of Technology (Boston, MA)

Dr. Viswanathan is a senior postdoctoral scientist in the laboratory of Dr. Leonard Guarente in the Department of Biology at MIT (Cambridge, MA).

Past Projects

Identify and characterize genetic and chemical suppressors of C. elegans fer-1 as a way to identify potential new therapeutic targets

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.