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

Gyda Bjornsdottir (), Erna V. Ivarsdottir, Kristbjorg Bjarnadottir, Stefania Benonisdottir, Sandra Sif Gylfadottir, Gudny A. Arnadottir, Rafn Benediktsson, Gisli Hreinn Halldorsson, Anna Helgadottir, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Ingileif Jonsdottir, Anna Margret Kristinsdottir, Olafur Th. Magnusson, Gisli Masson, Pall Melsted, Thorunn Rafnar, Asgeir Sigurdsson, Gunnar Sigurdsson, Astros Skuladottir, Valgerdur Steinthorsdottir, Unnur Styrkarsdottir, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Arnor Vikingsson, Daniel F. Gudbjartsson, Hilma Holm, Hreinn Stefansson, Unnur Thorsteinsdottir, Gudmundur L. Norddahl, Patrick Sulem, Thorgeir E. Thorgeirsson and Kari Stefansson ()
Additional contact information
Gyda Bjornsdottir: deCODE Genetics/Amgen, Inc.
Erna V. Ivarsdottir: deCODE Genetics/Amgen, Inc.
Kristbjorg Bjarnadottir: deCODE Genetics/Amgen, Inc.
Stefania Benonisdottir: deCODE Genetics/Amgen, Inc.
Sandra Sif Gylfadottir: Danish Pain Research Center/Aarhus University Hospital
Gudny A. Arnadottir: deCODE Genetics/Amgen, Inc.
Rafn Benediktsson: University of Iceland
Gisli Hreinn Halldorsson: deCODE Genetics/Amgen, Inc.
Anna Helgadottir: deCODE Genetics/Amgen, Inc.
Adalbjorg Jonasdottir: deCODE Genetics/Amgen, Inc.
Aslaug Jonasdottir: deCODE Genetics/Amgen, Inc.
Ingileif Jonsdottir: deCODE Genetics/Amgen, Inc.
Anna Margret Kristinsdottir: deCODE Genetics/Amgen, Inc.
Olafur Th. Magnusson: deCODE Genetics/Amgen, Inc.
Gisli Masson: deCODE Genetics/Amgen, Inc.
Pall Melsted: deCODE Genetics/Amgen, Inc.
Thorunn Rafnar: deCODE Genetics/Amgen, Inc.
Asgeir Sigurdsson: deCODE Genetics/Amgen, Inc.
Gunnar Sigurdsson: deCODE Genetics/Amgen, Inc.
Astros Skuladottir: deCODE Genetics/Amgen, Inc.
Valgerdur Steinthorsdottir: deCODE Genetics/Amgen, Inc.
Unnur Styrkarsdottir: deCODE Genetics/Amgen, Inc.
Gudmundur Thorgeirsson: deCODE Genetics/Amgen, Inc.
Gudmar Thorleifsson: deCODE Genetics/Amgen, Inc.
Arnor Vikingsson: Landspitali—The National University Hospital of Iceland
Daniel F. Gudbjartsson: deCODE Genetics/Amgen, Inc.
Hilma Holm: deCODE Genetics/Amgen, Inc.
Hreinn Stefansson: deCODE Genetics/Amgen, Inc.
Unnur Thorsteinsdottir: deCODE Genetics/Amgen, Inc.
Gudmundur L. Norddahl: deCODE Genetics/Amgen, Inc.
Patrick Sulem: deCODE Genetics/Amgen, Inc.
Thorgeir E. Thorgeirsson: deCODE Genetics/Amgen, Inc.
Kari Stefansson: deCODE Genetics/Amgen, Inc.

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09719-4

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