Back to Search Start Over

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

Authors :
Bjornsdottir, Gyda
Ivarsdottir, Erna V.
Bjarnadottir, Kristbjorg
Benonisdottir, Stefania
Gylfadottir, Sandra Sif
Arnadottir, Gudny A.
Benediktsson, Rafn
Halldorsson, Gisli Hreinn
Helgadottir, Anna
Jonasdottir, Adalbjorg
Jonasdottir, Aslaug
Jonsdottir, Ingileif
Kristinsdottir, Anna Margret
Magnusson, Olafur Th.
Masson, Gisli
Melsted, Pall
Rafnar, Thorunn
Sigurdsson, Asgeir
Sigurdsson, Gunnar
Skuladottir, Astros
Source :
Nature Communications; 4/16/2019, Vol. 10 Issue 1, pN.PAG-N.PAG, 1p
Publication Year :
2019

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. Diagnosis and classification of peripheral neuropathy (PN) is facilitated by nerve conduction (NC) studies. Here, Bjornsdottir et al. find a low-frequency PRPH splice-donor variant that associates with NC amplitude and neurological assessment of recalled PRPH variant carriers reveals increased risk of a mild sensory-negative PN. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20411723
Volume :
10
Issue :
1
Database :
Complementary Index
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
135910243
Full Text :
https://doi.org/10.1038/s41467-019-09719-4