A nonstop variant in REEP1 causes peripheral neuropathy by unmasking a 3'UTR-encoded, aggregation-inducing motif

Hum Mutat. 2018 Feb;39(2):193-196. doi: 10.1002/humu.23369. Epub 2017 Nov 27.


Single-nucleotide variants that abolish the stop codon ("nonstop" alterations) are a unique type of substitution in genomic DNA. Whether they confer instability of the mutant mRNA or result in expression of a C-terminally extended protein depends on the absence or presence of a downstream in-frame stop codon, respectively. Of the predicted protein extensions, only few have been functionally characterized. In a family with autosomal dominant Charcot-Marie-Tooth disease type 2, that is, an axonopathy affecting sensory neurons as well as lower motor neurons, we identified a heterozygous nonstop variant in REEP1. Mutations in this gene have classically been associated with the upper motor neuron disorder hereditary spastic paraplegia (HSP). We show that the C-terminal extension resulting from the nonstop variant triggers self-aggregation of REEP1 and of several reporters. Our findings support the recently proposed concept of 3'UTR-encoded "cryptic amyloidogenic elements." Together with a previous report on an aggregation-prone REEP1 deletion variant in distal hereditary motor neuropathy, they also suggest that toxic gain of REEP1 function, rather than loss-of-function as relevant for HSP, specifically affects lower motor neurons. A search for similar correlations between genotype, phenotype, and effect of mutant protein may help to explain the wide clinical spectra also in other genetically determined disorders.

Keywords: Charcot-Marie-Tooth disease; REEP1; aggregation; hereditary motor neuropathy; hereditary spastic paraplegia; motor neuron disorder; nonstop variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Charcot-Marie-Tooth Disease / genetics
  • Female
  • Genotype
  • Humans
  • Male
  • Membrane Transport Proteins / genetics*
  • Mutation / genetics
  • Pedigree
  • Peripheral Nervous System Diseases / genetics*
  • Phenotype
  • Spastic Paraplegia, Hereditary / genetics


  • 3' Untranslated Regions
  • Membrane Transport Proteins
  • REEP1 protein, human