Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: A window of opportunity in the search for genetic modifiers

Terry D. Heiman-Patterson, Roger B. Sher, Elizabeth A. Blankenhorn, Guillermo Alexander, Jeffrey S. Deitch, Catherine B. Kunst, Nicholas Maragakis, Gregory Cox

Research output: Contribution to journalReview articlepeer-review

Abstract

Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically. The most utilized and best characterized Tg mice are the G93A mutant hSOD1 (Tg(hSOD1-G93A)1GUR mice), abbreviated G93A. In this review we highlight what is known about background-dependent differences in disease phenotype in transgenic mice that carry mutated human or mouse SOD1. Expression of G93A-hSOD1Tg in congenic lines with ALR, NOD.Rag1KO, SJL or C3H backgrounds show a more severe phenotype than in the mixed (B6xSJL) hSOD1Tg mice, whereas a milder phenotype is observed in B6, B10, BALB/c and DBA inbred lines. We hypothesize that the background differences are due to disease-modifying genes. Identification of modifier genes can highlight intracellular pathways already suspected to be involved in motor neuron degeneration; it may also point to new pathways and processes that have not yet been considered. Most importantly, identified modifier genes provide new targets for the development of therapies.

Original languageEnglish (US)
Pages (from-to)79-86
Number of pages8
JournalAmyotrophic Lateral Sclerosis
Volume12
Issue number2
DOIs
StatePublished - Mar 1 2011

Keywords

  • Amyotrophic lateral sclerosis
  • genetic background
  • genetic modifiers

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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