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; Kari Stefansson

doi:10.1038/s41467-019-09719-4

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 SkuladottirValgerdur 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, Kari Stefansson

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin - Dansk Smerteforskningscenter

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

8 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	1777
Tidsskrift	Nature Communications
Vol/bind	10
Nummer	1
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-019-09719-4
Status	Udgivet - 2019

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10.1038/s41467-019-09719-4Licens: CC BY

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Citationsformater

Bjornsdottir, G., Ivarsdottir, E. V., Bjarnadottir, K., Benonisdottir, S., Gylfadottir, S. S., Arnadottir, G. A., Benediktsson, R., Halldorsson, G. H., Helgadottir, A., Jonasdottir, A., Jonasdottir, A., Jonsdottir, I., Kristinsdottir, A. M., Magnusson, O. T., Masson, G., Melsted, P., Rafnar, T., Sigurdsson, A., Sigurdsson, G., ... Stefansson, K. (2019). A PRPH splice-donor variant associates with reduced sural nerve amplitude and risk of peripheral neuropathy. Nature Communications, 10(1), Artikel 1777. https://doi.org/10.1038/s41467-019-09719-4

@article{509a157d50a74d03bc918b3705361a2c,

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

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.",

author = "Gyda Bjornsdottir and Ivarsdottir, {Erna V.} and Kristbjorg Bjarnadottir and Stefania Benonisdottir and Gylfadottir, {Sandra Sif} and Arnadottir, {Gudny A.} and Rafn Benediktsson and Halldorsson, {Gisli Hreinn} and Anna Helgadottir and Adalbjorg Jonasdottir and Aslaug Jonasdottir and Ingileif Jonsdottir and Kristinsdottir, {Anna Margret} and Magnusson, {Olafur Th} and Gisli Masson and Pall Melsted and Thorunn Rafnar and Asgeir Sigurdsson and Gunnar Sigurdsson and Astros Skuladottir and Valgerdur Steinthorsdottir and Unnur Styrkarsdottir and Gudmundur Thorgeirsson and Gudmar Thorleifsson and Arnor Vikingsson and Gudbjartsson, {Daniel F.} and Hilma Holm and Hreinn Stefansson and Unnur Thorsteinsdottir and Norddahl, {Gudmundur L.} and Patrick Sulem and Thorgeirsson, {Thorgeir E.} and Kari Stefansson",

year = "2019",

doi = "10.1038/s41467-019-09719-4",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Bjornsdottir, G, Ivarsdottir, EV, Bjarnadottir, K, Benonisdottir, S, Gylfadottir, SS, Arnadottir, GA, Benediktsson, R, Halldorsson, GH, Helgadottir, A, Jonasdottir, A, Jonasdottir, A, Jonsdottir, I, Kristinsdottir, AM, Magnusson, OT, Masson, G, Melsted, P, Rafnar, T, Sigurdsson, A, Sigurdsson, G, Skuladottir, A, Steinthorsdottir, V, Styrkarsdottir, U, Thorgeirsson, G, Thorleifsson, G, Vikingsson, A, Gudbjartsson, DF, Holm, H, Stefansson, H, Thorsteinsdottir, U, Norddahl, GL, Sulem, P, Thorgeirsson, TE & Stefansson, K 2019, 'A PRPH splice-donor variant associates with reduced sural nerve amplitude and risk of peripheral neuropathy', Nature Communications, bind 10, nr. 1, 1777. https://doi.org/10.1038/s41467-019-09719-4

A PRPH splice-donor variant associates with reduced sural nerve amplitude and risk of peripheral neuropathy. / Bjornsdottir, Gyda; Ivarsdottir, Erna V.; Bjarnadottir, Kristbjorg et al.
I: Nature Communications, Bind 10, Nr. 1, 1777, 2019.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - A PRPH splice-donor variant associates with reduced sural nerve amplitude and risk of peripheral neuropathy

AU - Bjornsdottir, Gyda

AU - Ivarsdottir, Erna V.

AU - Bjarnadottir, Kristbjorg

AU - Benonisdottir, Stefania

AU - Gylfadottir, Sandra Sif

AU - Arnadottir, Gudny A.

AU - Benediktsson, Rafn

AU - Halldorsson, Gisli Hreinn

AU - Helgadottir, Anna

AU - Jonasdottir, Adalbjorg

AU - Jonasdottir, Aslaug

AU - Jonsdottir, Ingileif

AU - Kristinsdottir, Anna Margret

AU - Magnusson, Olafur Th

AU - Masson, Gisli

AU - Melsted, Pall

AU - Rafnar, Thorunn

AU - Sigurdsson, Asgeir

AU - Sigurdsson, Gunnar

AU - Skuladottir, Astros

AU - Steinthorsdottir, Valgerdur

AU - Styrkarsdottir, Unnur

AU - Thorgeirsson, Gudmundur

AU - Thorleifsson, Gudmar

AU - Vikingsson, Arnor

AU - Gudbjartsson, Daniel F.

AU - Holm, Hilma

AU - Stefansson, Hreinn

AU - Thorsteinsdottir, Unnur

AU - Norddahl, Gudmundur L.

AU - Sulem, Patrick

AU - Thorgeirsson, Thorgeir E.

AU - Stefansson, Kari

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85064544852&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-09719-4

DO - 10.1038/s41467-019-09719-4

M3 - Journal article

C2 - 30992453

AN - SCOPUS:85064544852

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1777

ER -

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

Abstract

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