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

doi:10.1002/humu.24214

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

College of Medicine and Public Health

Research output: Contribution to journal › Article › peer-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 language	English
Number of pages	9
Journal	Human Mutation
DOIs	https://doi.org/10.1002/humu.24214
Publication status	E-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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Mullany, Sean ; Souzeau, Emmanuelle ; Klebe, Sonja ; Zhou, Tiger ; Knight, Lachlan S.W. ; Qassim, Ayub ; Berry, Ella C. ; Marshall, Henry ; Hussey, Matthew ; Dubowsky, Andrew ; Breen, James ; Hassall, Mark M. ; Mills, Richard A. ; Craig, Jamie E. ; Siggs, Owen M. / A novel GSN variant outside the G2 calcium-binding domain associated with Amyloidosis of the Finnish type. In: Human Mutation. 2021.

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

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.",

keywords = "Amyloidosis of the Finnish type, Finnish Amyloidosis, gelsolin, inherited corneal dystrophy, Meretoja syndrome, type II lattice dystrophy",

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

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: {\textcopyright} 2021 Wiley Periodicals LLC",

year = "2021",

month = may,

doi = "10.1002/humu.24214",

language = "English",

journal = "Human Mutation",

issn = "1059-7794",

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A novel GSN variant outside the G2 calcium-binding domain associated with Amyloidosis of the Finnish type. / Mullany, Sean; Souzeau, Emmanuelle ; Klebe, Sonja; Zhou, Tiger; Knight, Lachlan S.W.; Qassim, Ayub; Berry, Ella C.; Marshall, Henry; Hussey, Matthew; Dubowsky, Andrew; Breen, James; Hassall, Mark M.; Mills, Richard A.; Craig, Jamie E.; Siggs, Owen M.

In: Human Mutation, 05.2021.

Research output: Contribution to journal › Article › peer-review

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T1 - A novel GSN variant outside the G2 calcium-binding domain associated with Amyloidosis of the Finnish type

AU - Mullany, Sean

AU - Souzeau, Emmanuelle

AU - Klebe, Sonja

AU - Zhou, Tiger

AU - Knight, Lachlan S.W.

AU - Qassim, Ayub

AU - Berry, Ella C.

AU - Marshall, Henry

AU - Hussey, Matthew

AU - Dubowsky, Andrew

AU - Breen, James

AU - Hassall, Mark M.

AU - Mills, Richard A.

AU - Craig, Jamie E.

AU - Siggs, Owen M.

N1 - 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

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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.

KW - Amyloidosis of the Finnish type

KW - Finnish Amyloidosis

KW - gelsolin

KW - inherited corneal dystrophy

KW - Meretoja syndrome

KW - type II lattice dystrophy

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UR - http://purl.org/au-research/grants/NHMRC/1150144

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DO - 10.1002/humu.24214

M3 - Article

AN - SCOPUS:85105522338

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

ER -

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

Abstract

Bibliographical note

Keywords

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