CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis

Am J Hum Genet. 2023 Jul 6;110(7):1086-1097. doi: 10.1016/j.ajhg.2023.05.014. Epub 2023 Jun 19.


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.

Keywords: ALS; CGG repeat expansion; LRP12; OPDM; RNA foci; iPSCs; motor neuron; pTDP-43; repeat disease; skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / pathology
  • C9orf72 Protein / genetics
  • DNA Repeat Expansion
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Motor Neurons / pathology
  • Muscular Dystrophies* / genetics
  • Neurodegenerative Diseases* / genetics


  • C9orf72 Protein
  • LRP12 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1

Supplementary concepts

  • Oculopharyngodistal Myopathy