GSN – Familial Amyloidosis, Finnish Type

Familial amyloidosis, Finnish type (Meretoja syndrome) is an autosomal dominant systemic amyloidosis caused by point mutations in the gelsolin (GSN) gene, originally defined in Finnish kindreds. Initial linkage in five unrelated patients identified a G654A transition leading to a p.Asp163Asn substitution in the secreted gelsolin precursor (PMID:2175344). Subsequent reports in a Japanese pedigree demonstrated segregation of the identical mutation in 14 affected relatives across three generations with complete clinical co-segregation (PMID:8388189).

Affected individuals present in adulthood with a characteristic triad of progressive lattice corneal dystrophy, cutis laxa with facial diplegia (HP:0001349), and length-dependent peripheral polyneuropathy (HP:0001271). Systemic involvement may include orthostatic hypotension, cardiomyopathy, and renal amyloidosis documented in a series of 12 patients with nephrotic syndrome and chronic kidney disease (PMID:28139293).

Genetic evidence encompasses at least 34 probands across multiple independent families, including Finnish, Japanese, Argentinian (3 probands) (PMID:28924445), and sporadic renal cases. The recurrent c.487G>A (p.Asp163Asn) variant represents a mutational hotspot, with additional rare substitutions reported in other domains. Segregation analysis in the Japanese and Finnish pedigrees confirms full penetrance in adulthood.

Mechanistic studies reveal that Asp187Asn/Tyr mutations in domain 2 of gelsolin disrupt a critical Ca2+-binding site, destabilizing the fold and exposing a cryptic furin cleavage site in the trans-Golgi network. Aberrant proteolysis yields 71- and 53-residue amyloidogenic fragments that deposit extracellularly (PMID:14596804). Neuronal lineage cells preferentially generate the amyloid precursor, emphasizing a central role for neurons in pathogenesis (PMID:9632693).

In vitro and in vivo functional assays demonstrate that mutant gelsolin domains assemble into amyloid fibrils under acidic conditions without further proteolysis. Rescue studies using a domain-specific nanobody stabilize the G2 domain, reduce proteotoxicity in a Caenorhabditis elegans model, and underscore therapeutic potential (PMID:30625383).

Collectively, these data support a Definitive GSN–Finnish type amyloidosis association, with Strong genetic evidence (34 probands, segregation in 14 relatives) and Moderate functional evidence (extensive mechanistic and rescue studies). Key take-home: GSN molecular testing enables precise diagnosis, informs family counselling, and guides emerging therapies targeting aberrant proteolysis and amyloid assembly.

References

• The Journal of experimental medicine • 1990 • Mutation in gelsolin gene in Finnish hereditary amyloidosis. PMID:2175344
• Annals of neurology • 1993 • Inherited amyloid polyneuropathy type IV (gelsolin variant) in a Japanese family. PMID:8388189
• Case reports in ophthalmology • 2017 • The First Argentinian Family with Familial Amyloidosis of the Finnish Type. PMID:28924445
• Kidney international • 2017 • Clinical, biopsy, and mass spectrometry findings of renal gelsolin amyloidosis. PMID:28139293
• The Journal of biological chemistry • 1998 • Cells of the neuronal lineage play a major role in the generation of amyloid precursor fragments in gelsolin-related amyloidosis. PMID:9632693
• Journal of molecular biology • 2003 • Gelsolin domain 2 Ca2+ affinity determines susceptibility to furin proteolysis and familial amyloidosis of finnish type. PMID:14596804
• Biochimica et biophysica acta. Molecular basis of disease • 2019 • Nanobody interaction unveils structure, dynamics and proteotoxicity of the Finnish-type amyloidogenic gelsolin variant. PMID:30625383

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