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

Abstract

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.

Screening for REEP1 Mutations in 31 Chinese Hereditary Spastic Paraplegia Families

“…The Netherlands 7.4% in SPAST negative AD HSP (27 families and 110 cases) REEP1 is a causative gene of HSP and distal hereditary motor neuropathy type 5B (15), and REEP1-related diseases also include 2p11.2-2p12 deletion syndrome (16). The extension of the REEP1 protein and mislocalized REEP1 can lead to "toxic gain of function" and result in dHMN (15,17), whereas loss of function may lead to HSP (5)(6)(7).…”

“…More than 70 REEP1-related HSP pedigrees have been reported (7,9,14,15,17,20,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), and their genotypes and phenotypes are summarized in Supplementary Table 4. There is generally an early age at onset, commonly 0-20 and 30-35 years of age (14).…”

A gene expression signature‐based nomogram model in prediction of breast cancer bone metastases

“…REEP1 protein, which is preferentially expressed in neuronal and neuronal‐like exocytotic tissues like brain, spinal cord, and testes and localized to endoplasmic reticulum (ER) and plasma membranes, is a member of a family of ER shaping proteins . It has been found that REEP1 could facilitate mitochondrial‐ER interactions, which may result in intracellular Ca 2+ overload and axonal damage, and REEP1 variants were recognized as causes of Neurological Disease like hereditary spastic paraplegia (HSP) and distal hereditary motor neuropathy (dHMN) . The third gene SPIB, encoding an ETS‐domain transcription factor, was believed to be associated with cancers especially in lymphomas .…”

“…34,35 It has been found that REEP1 could facilitate mitochondrial-ER interactions, which may result in intracellular Ca 2+ overload and axonal damage, 36 and REEP1 variants were recognized as causes of Neurological Disease like hereditary spastic paraplegia (HSP) and distal hereditary motor neuropathy (dHMN). 37 The third gene SPIB, encoding an ETS-domain transcription factor, was believed to be associated with cancers especially in lymphomas. 38,39 Also, Yi-Jung et al 40 found the SPIB may be involved in tumorigenesis in live cancer, and Wei et al 41 reported that SPIB is expressed in invasive cancer cells in human primary lung cancer tissues.…”

Erbliche spastische Spinalparalysen: aktuelle Erkenntnisse und Entwicklungen

“…Interessanterweise handelt es sich dabei fast ausschließlich um Veränderungen im C-Terminus. Eine Genotyp-Phänotyp-Korrelation wäre damit direkt an die Primärstruktur des Proteins geknüpft [31].…”