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.

Diagnostic yield of candidate genes in an Australian corneal dystrophy cohort

“…All four individuals had systemic features consistent with a diagnosis of amyloidosis of the Finnish type, including drooping eyelids, dry skin, cutis laxa and eczema. Amyloid deposition was present in the anterior corneal stroma in the excised cornea of the proband and immunohistochemistry reported the presence of the GSN protein within corneal amyloid deposits (Mullany et al, 2021). We did not achieve a molecular diagnosis in the other four probands (CDSA188, CDSA249, CDSA289 & CDSA350).…”

A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation

“…At the time when this manuscript was being finalised, a novel pathological variant, W466R, was identified in the same S-π motif in G4 ( Fig. 6 C) [49] . This variant causes a clinical phenotype similar to M517R, E553K and the classical D187N/Y mutations, including corneal lattice dystrophy, cutis laxa and peripheral neuropathy.…”

Gelsolin Can Be a Prognostic Biomarker and Correlated with Immune Infiltrates in Gastric Cancer

“… 14 Recently, some case reports even found that a patient encounters renal gelsolin amyloidosis with the p.Asp174Asn mutation in the GSN gene, another with the phenotype of amyloidosis of the Finnish type because of GSN variant. 15 , 16 …”