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Somatic and intergenerational G4C2 hexanucleotide repeat instability in a human C9orf72 knock-in mouse model.

Nada Kojak1, Junko Kuno1, Kristina E Fittipaldi1

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A novel mouse model reveals two mechanisms of G4C2 repeat expansion in C9orf72 gene mutations linked to ALS and FTD. Mismatch repair drives minor expansions, while DNA breaks trigger major expansions via homology-directed repair.

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Area of Science:

  • Genetics and Molecular Biology
  • Neurodegenerative Diseases
  • Genomic Instability

Background:

  • C9orf72 gene G4C2 repeat expansions are a primary cause of familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).
  • Understanding the mechanisms of repeat instability is crucial for developing therapeutic strategies for these devastating neurological disorders.
  • Existing models do not fully recapitulate the complex repeat expansion dynamics observed in patients.

Purpose of the Study:

  • To develop and characterize a novel mouse model for studying C9orf72 G4C2 repeat instability.
  • To elucidate the distinct molecular pathways driving repeat expansion in both somatic and intergenerational contexts.
  • To investigate the role of DNA repair pathways in regulating repeat length changes.

Main Methods:

  • Creation of a transgenic mouse model harboring 96 copies of humanized G4C2 repeats at the C9orf72 locus.
  • Analysis of repeat expansion in mouse embryonic stem cells and in vivo using induced DNA double- and single-strand breaks (DSBs/SSBs).
  • Investigation of the involvement of mismatch repair (MMR) and homology-directed repair (HDR) pathways.

Main Results:

  • Two modes of repeat expansion were identified: minor expansions dependent on Msh2 (MMR pathway) and major expansions dependent on HDR when DSBs/SSBs were introduced.
  • Somatic repeat expansion in mice was primarily driven by the Msh2-dependent pathway.
  • Significant repeat expansions occurred in one-cell embryos upon SSB induction and intergenerationally when repeat copy number exceeded 400, suggesting a threshold effect.

Conclusions:

  • The novel mouse model effectively recapitulates C9orf72 G4C2 repeat expansion mechanisms.
  • DNA repair pathways, particularly MMR and HDR, play critical roles in regulating repeat instability.
  • Findings offer insights into the pathogenesis of C9orf72-linked ALS/FTD and provide a platform for future research.