Format

Send to

Choose Destination
Nat Commun. 2019 Apr 16;10(1):1777. doi: 10.1038/s41467-019-09719-4.

A PRPH splice-donor variant associates with reduced sural nerve amplitude and risk of peripheral neuropathy.

Author information

1
deCODE Genetics/Amgen, Inc., 101 Reykjavik, Iceland. gyda.bjornsdottir@decode.is.
2
deCODE Genetics/Amgen, Inc., 101 Reykjavik, Iceland.
3
School of Engineering and Natural Sciences, University of Iceland, 101 Reykjavik, Iceland.
4
Danish Pain Research Center/Aarhus University Hospital, 8000 Aarhus, Denmark.
5
Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
6
Landspitali-The National University Hospital of Iceland, 101 Reykjavik, Iceland.
7
deCODE Genetics/Amgen, Inc., 101 Reykjavik, Iceland. kari.stefansson@decode.is.
8
Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland. kari.stefansson@decode.is.

Abstract

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center