Bock AS1, Günther S1, Mohr J2, Goldberg LV1, Jahic A1, Klisch C3, Hübner CA4, Biskup S2, Beetz C1.
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.
Zur Journal of Human Mutation Publikation
- Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
- CeGaT GmbH und Praxis für Humangenetik, Tübingen, Germany.
- Neurologische Praxis Klisch, Erfurt, Germany.
- Department of Human Genetics, Jena University Hospital, Jena, Germany.