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

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

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.

Original languageEnglish
Article number1777
JournalNature Communications
Volume10
Issue1
ISSN2041-1723
DOIs
Publication statusPublished - 2019

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