Publisher's version (útgefin grein).Nerve conduction (NC) studies generate measures of peripheral nerve function that can reveal underlying pathology due to axonal loss, demyelination or both. We perform a genome-wide association study of sural NC amplitude and velocity in 7045 Icelanders and find a low-frequency splice-donor variant in PRPH (c.996+1G>A; MAF = 1.32%) associating with decreased NC amplitude but not velocity. PRPH encodes peripherin, an intermediate filament (IF) protein involved in cytoskeletal development and maintenance of neurons. Through RNA and protein studies, we show that the variant leads to loss-of-function (LoF), as when over-expressed in a cell line devoid of other IFs, it does not allow formation of the normal filamentous structure of peripherin, yielding instead punctate protein inclusions. Recall of carriers for neurological assessment confirms that from an early age, homozygotes have significantly lower sural NC amplitude than non-carriers and are at risk of a mild, early-onset, sensory-negative, axonal polyneuropathy.We thank all participants in deCODE studies for their valuable contribution to research, especially the participants of the deCODE Health Study and the deCODE Study on Genetics of Chronic and Neuropathic Pain. We also thank the research staff at the Patient Recruitment Center, and all colleagues who contributed to phenotype ascertainment, recruitment, collection of data, sample handling, and genotyping. The financial support from the European Commission to the NeuroPain project (FP7#HEALTH-2013-602891-2) and the National Institutes of Health (R01DE022905) is acknowledged.Peer Reviewe
