Clinical and Histopathological Features of Gelsolin Amyloidosis Associated with a Novel <i>GSN</i> Variant p.Glu580Lys

• Main Authors: Maja Potrč, Marija Volk, Matteo de Rosa, Jože Pižem, Nataša Teran, Helena Jaklič, Aleš Maver, Brigita Drnovšek-Olup, Michela Bollati, Katarina Vogelnik, Alojzija Hočevar, Ana Gornik, Vladimir Pfeifer, Borut Peterlin, Marko Hawlina, Ana Fakin
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: International Journal of Molecular Sciences
• Subjects: gelsolin amyloidosis; Meretoja syndrome; lattice corneal dystrophy; optic neuropathy; <i>GSN</i>; cutis laxa
• Online Access: https://www.mdpi.com/1422-0067/22/3/1084

Gelsolin amyloidosis typically presents with corneal lattice dystrophy and is most frequently associated with pathogenic <i>GSN</i> variant p.Asp214Asn. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel <i>GSN</i> variant p.Glu580Lys. We studied DNA samples of seven members of a two-generation family. Exome sequencing was performed in the proband, and targeted Sanger sequencing in the others. The heterozygous <i>GSN</i> variant p.Glu580Lys was identified in six patients. The patients exhibited corneal dystrophy (5/6), loose skin (5/6) and/or heart arrhythmia (3/6) and one presented with bilateral optic neuropathy. The impact of the mutation on the protein structure was evaluated in silico. The substitution is located in the fifth domain of gelsolin protein, homologous to the second domain harboring the most common pathogenic variant p.Asp214Asn. Structural investigation revealed that the mutation might affect protein folding. Histopathological analysis showed amyloid deposits in the skin. The p.Glu580Lys is associated with corneal dystrophy, strengthening the association of the fifth domain of gelsolin protein with the typical amyloidosis phenotype. Furthermore, optic neuropathy may be related to the disease and is essential to identify before discussing corneal transplantation.