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

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.

Modulation of soleus H-reflexes during gait in children with cerebral palsy.

In healthy adults, soleus H-reflexes are rhythmically modulated and generally depressed during gait compared with rest. From ages 6 to 13 yr, there is a progressive increase in the tonic inhibition of H-reflexes during walking, especially during the stance phase of the step cycle. In adults, rhythmic modulation and tonic depression are severely disturbed after bilateral spinal lesions but remain partly preserved after unilateral cerebral lesions. Children with diplegic cerebral palsy (CP) suffer from a bilateral supraspinal lesion of the corticospinal tract that occurs before the maturation of the CNS is complete. If supraspinal structures are involved in the tonic, but not rhythmic, age-dependent reflex depression, it could be hypothesized that the tonic reflex depression with age is disturbed in CP, whereas the rhythmic part of the modulation remains unaffected. To test this hypothesis, soleus H-reflexes were assessed during gait in 16 CP children aged 5-11 and 15-16 and compared with 25 age-matched healthy children walking at similar velocities. Although the rhythmic part of the modulation pattern was present in CP, there was no significant tonic reflex depression with age, thus reflecting a lack of maturation of the corticospinal tract. It is argued the rhythmic part of the modulation may be generated on a spinal or brain stem level and is therefore not affected by the bilateral supraspinal lesion, whereas the tonic depression that occurs with maturation of the CNS is under supraspinal control. In conclusion, the supraspinal structures affected in CP are therefore likely involved in this age-dependent tonic depression.