HGNC Approved Gene Symbol: GSN
SNOMEDCT: 783160006;
Cytogenetic location: 9q33.2 Genomic coordinates (GRCh38) : 9:121,201,483-121,332,842 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q33.2 | Amyloidosis, Finnish type | 105120 | Autosomal dominant | 3 |
Gelsolin, a protein of leukocytes, platelets, and other cells, severs actin filaments in the presence of submicromolar calcium, thereby solating cytoplasmic actin gels. A calcium-independent mechanism reverses the process. A gelsolin variant with 23 more N-terminal amino acids is a plasma component probably involved in the clearance of actin, the most abundant human protein, from the circulation. Kwiatkowski et al. (1986) isolated a full-length plasma gelsolin cDNA clone. Northern blot analysis suggested that a single gene encodes both cell and plasma gelsolins. This protein may be unique in that it is made for both secretion and intracytoplasmic location.
By Southern blot analysis of somatic cell hybrids and in situ chromosomal localization, Kwiatkowski et al. (1988) demonstrated that the GSN gene is located on 9q32-q34. In situ hybridization to cells containing a Philadelphia chromosome, as well as Southern blot analysis of a chronic myeloid leukemia cell DNA, indicated that GSN is centromeric to ABL (189980), which is located in 9q34. Furthermore, Southern blot analysis of NotI-digested, pulsed-field gel electrophoresis-separated DNA indicated that GSN is 40 or more kb centromeric to ABL. Pilz et al. (1992) used interspecies backcrosses to map the Gsn gene to mouse chromosome 2.
Maury et al. (1990) identified amino acid homology between gelsolin and the amyloid of the Finnish variety of amyloidosis (105120). Haltia et al. (1990) likewise showed that the amyloid in this disorder is antigenically and structurally related to gelsolin. Gelsolin is also known as brevin, or actin-depolymerizing factor; it is the principal intracellular and extracellular actin-severing protein. Gelsolin and Gc protein (GC; 139200) together constitute the extracellular actin-scavenger system (Lee and Galbraith, 1992) which prevents the toxic effects of actin release into the extracellular space under circumstances of cell necrosis.
Vasconcellos et al. (1994) showed that the viscous sputum from patients with cystic fibrosis (219700) contains filamentous actin derived from leukocytes and that gelsolin, which severs actin filaments, rapidly decreases the viscosity of CF sputum samples in vitro. They suggested that gelsolin may have therapeutic potential as a mucolytic agent in CF patients.
Caspase-mediated proteolysis is a critical and central element of the apoptotic process; therefore, it was important to identify the downstream molecular targets of caspases. Kamada et al. (1998) established a method for cloning the genes of caspase substrates by 2 major modifications of the yeast 2-hybrid system: (1) both large and small subunits with active caspases were expressed in yeast under ADH1 (103700) promoters and the small subunit was fused to the LexA DNA-binding domain; and (2) a point mutation was introduced that substituted serine for the active site cysteine and thereby prevented proteolytic cleavage of the substrates, possibly stabilizing the enzyme-substrate complexes in yeast. After screening a mouse embryo cDNA expression library by using the bait plasmid for caspase-3, Kamada et al. (1998) obtained 13 clones that encoded proteins binding to caspase-3, and showed that 10 clones, including gelsolin, an actin-regulatory protein implicated in apoptosis, were cleaved by recombinant caspase-3 in vitro. Using the same bait, they also isolated human gelsolin cDNA from a human thymus cDNA expression library. They showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at asp352 (D352) in a 5-amino acid sequence, DQTD(352)G, findings consistent with previous observations on murine gelsolin. In addition, Kamada et al. (1998) ascribed the antiapoptotic activity of gelsolin to prevention of a step leading to cytochrome c release from the mitochondria into the cytosol. The results demonstrated the usefulness of this cloning method for identification of the substrates of caspases and possibly of other other enzymes.
To investigate the pathogenic mechanisms in gelsolin-related amyloidosis, Paunio et al. (1994) transfected mammalian mesenchymal COS-1 cells with a derivative of an expression vector containing cDNA coding for the wildtype (D187) and mutant forms (N187 and Y187) of plasma gelsolin. Both disease-associated mutant forms of gelsolin were found to be abnormally processed, resulting in the secretion of an aberrant 68-kD gelsolin fragment into the culture medium. This fragment probably represented a carboxy-terminal part of the protein and contained the suggested amyloid-forming sequence.
In a functional genomic screen using RNA interference to identify human genes involved in ciliogenesis control, Kim et al. (2010) identified 2 gelsolin family proteins, GSN and AVIL (613397), which regulate cytoskeletal actin organization by severing actin filaments. Depletion of GSN proteins by 2 independent siRNAs significantly reduced ciliated cell numbers, indicating that actin filament severing is involved in ciliogenesis. In contrast, silencing of actin-related protein ACTR3 (604222), which is a major constituent of the ARP2/3 complex that is necessary for nucleating actin polymerization at filament branches, caused a significant increase in cilium length and also facilitated ciliogenesis independently of serum starvation. Kim et al. (2010) concluded that their observations indicated an inhibitory role of branched actin network formation in ciliogenesis.
A single-nucleotide mutation at residue 187 (either D187N 137350.0001 or D187Y 137350.0002) in Finnish amyloidosis occurs within domain 2 of the actin-regulating protein gelsolin. The mutation somehow allows a masked cleavage site to be exposed, leading to the first step in the formation of an amyloidogenic fragment. Kazmirski et al. (2000) performed nuclear magnetic resonance (NMR) experiments investigating structural and dynamic changes between wildtype and the D187N gelsolin domain 2. From their observations, Kazmirski et al. (2000) proposed that the D187N mutation destabilizes the C-terminal tail of domain 2 resulting in a more exposed cleavage site and leading to the first proteolysis step in the formation of the amyloidogenic fragment.
Kazmirski et al. (2002) determined the structure of domain 2 (D2, residues 151-266) of gelsolin and found that asp187 is part of a bivalent cadmium ion metal-binding site. Two bivalent calcium ions are required for a conformational transition of gelsolin to its active form. Kazmirski et al. (2002) showed that the cadmium-binding site in D2 is one of these 2 calcium-binding sites and is essential to the stability of D2. Mutation of asp187 to asn (127350.0001) disrupted calcium binding in D2, leading to instability upon calcium activation. Instability makes the domain a target for aberrant proteolysis, thereby enacting the first step in the cascade leading to familial amyloidosis, Finnish type.
A single-nucleotide mutation at residue 187, either D187N (137350.0001) or D187Y (137350.0002), within domain 2 of the actin-regulating protein gelsolin was identified in patients with Finnish amyloidosis (19:Maury et al., 1990; de la Chapelle et al., 1992).
In 6 members of a family with Finnish-type amyloidosis, Potrc et al. (2021) identified a heterozygous missense mutation in the GSN gene (E580K; 137350.0003). The mutation, which was found by exome sequencing, segregated with disease in the family and was not present in the gnomAD database. The affected residue was located in the G5 domain, which is homologous to the second domain, which contains D187N (137350.0001), the most common pathogenic variant.
In 2 unrelated families segregating Finnish-type amyloidosis, one with a single affected person and the other with 3 affected first-degree relatives, Mullany et al. (2021) identified heterozygous mutations in the GSN gene. In the single affected person, the classic D187N mutation (also referred to as D214N) was identified. In the 3 affected family members (father, son, and daughter), a trp493-to-arg (W493R; 137350.0004) mutation was identified. The W493R variant was the first to be located in the G4 domain. Immunohistochemical studies on corneal tissue from the proband in the family with the W493R mutation identified gelsolin protein within histologically defined corneal amyloid deposits.
To investigate the in vivo function of gelsolin, Witke et al. (1995) generated transgenic gelsolin-null mice. Although embryonic development and longevity were normal, platelet shape changes were decreased in the Gsn-null mice, causing prolonged bleeding times. Neutrophil migration in vivo into peritoneal exudates and in vitro was delayed. Dermal fibroblasts had excessive actin stress fibers and migrated more slowly than wildtype fibroblasts, but had increased contractility in vitro. The observations established the requirement of gelsolin for rapid motile responses in cell types involved in stress responses, such as hemostasis, inflammation, and wound healing. Neither gelsolin nor other proteins with similar actin filament-severing activity are expressed in early embryonic cells, which indicated that this mechanism of actin filament dynamics is not essential for motility during early embryogenesis.
The amyloid protein in the Finnish type of hereditary amyloidosis (105120), also known as the Meretoja type, is a fragment of the actin-filament binding region of a variant gelsolin molecule. Using PCR and allele-specific oligonucleotide hybridization analysis of genomic DNA, Maury et al. (1990) identified a single base mutation, 654G-A. This nucleotide substitution was found in all 5 unrelated patients with Finnish amyloidosis studied but not in 45 unrelated control subjects. They were guided in the development of the allele-specific oligonucleotide hybridization method by the demonstration that the amyloid protein in this disorder has an asp187-to-asn mutation (D187N) (Maury (1990, 1991)) resulting from the change of GAC to AAC. Ghiso et al. (1990) and Levy et al. (1990) likewise identified the D187N change. Hiltunen et al. (1991) found the D187N mutation in affected members of 3 large families in restricted areas on the southern coast of Finland. Maury (1991) found the D187N mutation in 6 other ostensibly unrelated Finnish families. These included 2 sibs, the offspring of 2 affected parents, who were by DNA test homozygous for the mutation and showed unusually early onset and severity of the disease (Maury, 1993). Proteinuria was present by the teens and amyloid nephropathy with nephrotic syndrome by the 20s. Hemodialysis and renal transplant were necessary in the 30s. Contrariwise, in the course of family studies, Maury (1991) found 30-year-old asymptomatic individuals with the mutation but with changes of lattice corneal dystrophy on examination. (Meretoja (1973) had suggested that 2 patients who were more severely affected than the average, and whose parents were affected, represented homozygosity for this gene.)
Maury (1991) and de la Chapelle et al. (1992) demonstrated the same D187N mutation in the American family of Scottish extraction reported by Sack et al. (1981). Maury et al. (1992) presented molecular evidence of homozygosity in 1 such patient. It appears that these were independent mutations. This disorder is extraordinarily rare except in Finland where peculiar historical and demographic factors have been responsible for the high frequency; if all the cases prove to be due to the asp187-to-asn mutation, then it would seem likely that the change in the amino acid sequence at that particular site of the gelsolin molecule is particularly critical, perhaps uniquely critical, to rendering gelsolin amyloidogenic. Gorevic et al. (1991) found the asp187-to-asn mutation in an American patient of Irish descent and his affected 31-year-old daughter. This family had been reported by Purcell et al. (1983). Haltia et al. (1992) described a slot-blot analysis for the asp187-to-asn mutation. Paunio et al. (1992) applied the solid-phase minisequencing test to determine the nature of the mutation in 94 affected persons and 32 healthy family members from 55 families with the Finnish type of familial amyloidosis living in Finland. The families represented about 34% (55/160) of all known affected families in Finland. In all affected individuals, they found the asp187-to-asn gene. Furthermore, they found the mutation in 54% (20/37) of young at-risk persons with the mutation. Sunada et al. (1993) found the same mutation as the cause of the Finnish or Meretoja type of amyloid polyneuropathy in 14 members of a large Japanese kindred with no known contacts with Finnish or other Caucasian populations. This further supports the notion that the asp187-to-asn mutation or other mutations at the same location are specifically amyloidogenic.
Steiner et al. (1995) used a PCR-based DNA assay to identify the same G-to-A mutation at position 654 of the GSN gene in an American kindred with Scandinavian ancestry. The mutation was demonstrated in the clinically affected proband, her deceased clinically affected father, and her presumably affected presymptomatic son. The diagnosis of Finnish-type amyloidosis had been made in the proband after the recognition of lattice corneal dystrophy on routine ophthalmologic examination at age 34. At the age of 38, she was asymptomatic with normal vision and no evidence of cranial nerve dysfunction, no peripheral neuropathy, and no evidence of cardiac or renal dysfunction. The father died at age 77 from complications of systemic amyloidosis diagnosed 9 years before his death. Manifestations of disease included lattice corneal dystrophy, facial muscle weakness with lagophthalmos and sagging facial skin, cardiomyopathy with left ventricular hypertrophy, and aortic root dilatation, chronic renal insufficiency, hypothyroidism, and pancytopenia.
From haplotype analysis in 10 Finnish and 2 Japanese families with the Finnish type of familial amyloidosis, Paunio et al. (1995) demonstrated a uniform disease haplotype in all the disease-associated chromosomes of the Finnish families which was different from the one observed in the Japanese families. Thus, they concluded that these mutations arose independently.
Sipila and Aula (2002) reported the creation of an up-to-date database for mutations of Finnish disease heritage, i.e., the more than 30 monogenic disorders that are more prevalent in the Finnish population than in the rest of the world. They noted that all Finnish cases of familial amyloidosis of the Finnish type have had the D187N mutation.
De la Chapelle et al. (1992) identified the characteristic asp187-to-asn mutation due to a 654G-A transition in the GSN gene in a Dutch family with the clinically typical corneocranial type of amyloidosis.
In an Australian patient with Finnish-type amyloidosis, Mullany et al. (2021) identified heterozygosity for the D187N mutation in the GSN gene.
Mullany et al. (2021) stated that this variant is also referred to as ASP214ASN (NM_000177.5).
De la Chapelle et al. (1992) found a heterozygous 654G-T transversion in GSN predicting an asp187-to-tyr substitution (D187Y) in a Danish family and a Czech family with the Finnish-type of amyloidosis (105120). Different haplotypes were found in the Danish and Czech families, suggesting that the mutations arose independently. The substitution of an uncharged polar amino acid for the acidic aspartic acid at residue 187 creates a beta sheet conformation that may be preferentially or uniquely amyloidogenic for gelsolin.
Mullany et al. (2021) stated that this variant is also referred to as ASP214TYR (NM_000177.5).
In 6 members of a family with Finnish-type amyloidosis (105120), Potrc et al. (2021) identified a heterozygous c.1738G-A transition (c.1738G-A, NM_000177.5) in the GSN gene, resulting in a glu580-to-lys (E580K) substitution. The variant segregated with the disease in the family and was not present in the gnomAD database. The affected residue was located in the G5 domain, which is homologous to the second domain, which contains D187N (137350.0001), the most common pathogenic variant.
In a father, son, and daughter from an Australian family with Finnish-type amyloidosis (105120), Mullany et al. (2021) identified a c.1477T-C transition (c.1477T-C, NM_000177.5) in the GSN gene, resulting in a trp493-to-arg (W493R) substitution at a highly conserved residue. This variant was not present in public variant databases. The W93R variant was the first to be located in the G4 domain. Immunohistochemical studies on corneal tissue from the proband identified gelsolin protein within histologically defined corneal amyloid deposits.
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