FAN1 modifies Huntington's disease progression by stabilizing the expanded HTT CAG repeat

Hum Mol Genet. 2019 Feb 15;28(4):650-661. doi: 10.1093/hmg/ddy375.

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the huntingtin (HTT) gene. CAG repeat length explains around half of the variation in age at onset (AAO) but genetic variation elsewhere in the genome accounts for a significant proportion of the remainder. Genome-wide association studies have identified a bidirectional signal on chromosome 15, likely underlain by FANCD2- and FANCI-associated nuclease 1 (FAN1), a nuclease involved in DNA interstrand cross link repair. Here we show that increased FAN1 expression is significantly associated with delayed AAO and slower progression of HD, suggesting FAN1 is protective in the context of an expanded HTT CAG repeat. FAN1 overexpression in human cells reduces CAG repeat expansion in exogenously expressed mutant HTT exon 1, and in patient-derived stem cells and differentiated medium spiny neurons, FAN1 knockdown increases CAG repeat expansion. The stabilizing effects are FAN1 concentration and CAG repeat length-dependent. We show that FAN1 binds to the expanded HTT CAG repeat DNA and its nuclease activity is not required for protection against CAG repeat expansion. These data shed new mechanistic insights into how the genetic modifiers of HD act to alter disease progression and show that FAN1 affects somatic expansion of the CAG repeat through a nuclease-independent mechanism. This provides new avenues for therapeutic interventions in HD and potentially other triplet repeat disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Exodeoxyribonucleases / genetics*
  • Exons / genetics
  • Gene Knockdown Techniques
  • Genome-Wide Association Study
  • Humans
  • Huntingtin Protein / genetics*
  • Huntington Disease / genetics*
  • Huntington Disease / pathology
  • Mice
  • Neurons / metabolism
  • Neurons / pathology
  • Transcriptome / genetics*
  • Trinucleotide Repeat Expansion / genetics

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Exodeoxyribonucleases
  • FAN1 protein, human