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

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
Number of pages9
JournalHuman Mutation
DOIs
Publication statusE-pub ahead of print - May 2021

Bibliographical note

Funding Information:
The authors thank Angela Chappell and Carly Emerson (Flinders Medical Centre) for ophthalmic photography, and Pat Vilimas (Flinders Health and Medical Research Institute) for electron microscopy. The work was funded by the Ophthalmic Research Institute of Australia and National Health (ORIA) and Medical Research Council (NHMRC program grant APP1150144 and project grant APP1157571). Jamie E. Craig was supported by an NHMRC Practitioner Fellowship. Emmanuelle Souzeau was supported by an Early Career Fellowship from the Hospital Research Foundation. Sean Mullany was supported by a Flinders Medical Centre Clinician's Special Purpose Fund (CSPF) Scholarship.

Publisher Copyright:
© 2021 Wiley Periodicals LLC

Keywords

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

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