A novel GSN variant outside the G2 calcium-binding domain associated with Amyloidosis of the Finnish type

Sean Mullany, Emmanuelle Souzeau, Sonja Klebe, Tiger Zhou, Lachlan S.W. Knight, Ayub Qassim, Ella C. Berry, Henry Marshall, Matthew Hussey, Andrew Dubowsky, James Breen, Mark M. Hassall, Richard A. Mills, Jamie E. Craig, Owen M. Siggs

    Research output: Contribution to journalArticlepeer-review

    2 Citations (Scopus)

    Abstract

    Gelsolin (GSN) variants have been implicated in amyloidosis of the Finnish type. This case series reports a novel GSN:c.1477T>C,p.(Trp493Arg) variant in a family with ocular and systemic features consistent with Finnish Amyloidosis. Exome sequencing performed on affected individuals from two families manifesting cutis laxa and polymorphic corneal stromal opacities demonstrated the classic GSN:c.654G>A,p.Asp214Asn variant in single affected individual from one family, and a previously undocumented GSN:c.1477T>C variant in three affected first-degree relatives from a separate family. Immunohistochemical studies on corneal tissue from a proband with the c.1477T>C variant identified gelsolin protein within histologically defined corneal amyloid deposits. This study reports a novel association between the predicted pathogenic GSN:c.1477T>C variant and amyloidosis of the Finnish type, and is the first to provide functional evidence of a pathological GSN variant at a locus distant to the critical G2 calcium-binding region, resulting in the phenotype of amyloidosis of the Finnish type.

    Original languageEnglish
    Pages (from-to)818-826
    Number of pages9
    JournalHuman mutation
    Volume42
    Issue number7
    DOIs
    Publication statusPublished or Issued - Jul 2021

    Keywords

    • Amyloidosis of the Finnish type
    • Finnish Amyloidosis
    • Meretoja syndrome
    • gelsolin
    • inherited corneal dystrophy
    • type II lattice dystrophy

    ASJC Scopus subject areas

    • Genetics
    • Genetics(clinical)

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