Alternative titles; symbols
HGNC Approved Gene Symbol: CSTA
Cytogenetic location: 3q21.1 Genomic coordinates (GRCh38): 3:122,325,248-122,341,969 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21.1 | Peeling skin syndrome 4 | 607936 | Autosomal recessive | 3 |
Cystatin A is a cysteine proteinase inhibitor that belongs to family 1 of the cystatin superfamily. It was originally derived from the cytosol of human polymorphonuclear granulocytes (Strauss et al., 1988) but has also been isolated from the spleen, liver, and epidermis. Cystatin A is identical to keratolinin, one of the precursor proteins of the cornified cell envelope of keratinocytes (Takahashi et al., 1998).
Strauss et al. (1988) isolated a DNA containing the coding sequence for human stefin A by enzymic ligation of chemically synthesized deoxyoligonucleotides, using the Khorana ligation method. The deduced 98-residue protein has a molecular mass of 11 kDa. It forms tight complexes with papain and the cathepsins B, H, and L. Expression in E. coli resulted in secretion of a protein exhibiting biologic properties similar to those of the native protein isolated from human plasma.
By immunostaining normal skin sections, Blaydon et al. (2011) demonstrated localization of cystatin A throughout all suprabasal layers of the epidermis with a diffuse cytoplasmic distribution and the strongest synthesis in the granular layer.
Takahashi et al. (1998) determined that the CSTA gene contains 3 exons.
Hsieh et al. (1991) used PCR to amplify the human stefin A sequence in a panel of rodent-human somatic cell hybrid DNAs. They identified STF1 sequences on chromosome 3. Sublocalization to human 3q21 was accomplished using a deletion mapping panel for human chromosome 3.
Tsui et al. (1993) studied 3 members of the murine stefin gene family. Southern analysis suggested that the family comprises at least 6 and possibly 10 to 20 members, all of which appear to be clustered in the proximal region of mouse chromosome 16 in an area of conserved homology of synteny with human chromosome 3q.
Takahashi et al. (1992) demonstrated that phosphorylated cystatin A is a component of the cornified envelope proteins in newborn rat skin. Incubation of both phosphorylated cystatin A and nonphosphorylated cystatin A with epidermal transglutaminase (TGM1; 190195) resulted in production of polymerized proteins formed by crosslinking peptide bonds between lysine residues of cystatin A and glutamine residues of the substrate protein. Inhibition of protein kinase C inhibited incorporation of cystatin A into keratohyaline granules, indicating that phosphorylation of cystatin A is necessary to target the polymerized protein to the cornified envelope.
Blaydon et al. (2011) knocked down cystatin A in the HaCaT human keratinocyte cell line and studied the effects of mechanical stress on these cells. Upon intense stretching, thickening of keratin filaments was observed in both knockdown and control cells; however, in the knockdown cells, the monolayer of cells split into many fragments, whereas the monolayer was intact in control cells. At higher magnification, breakage of keratin filaments and widened intercellular spaces could be seen in the CSTA knockdown cells. In contrast, there were no obvious cell-cell adhesion defects in the stretched control cell monolayer. Knockdown cell monolayers subjected to agitation by inversion showed a high increase in the number of fragments, compared to the very few fragments obtained for the control monolayers. In an organotypic 3D culture model, Blaydon et al. (2011) demonstrated that there is no gross barrier defect associated with CSTA knockdown. Blaydon et al. (2011) concluded that cystatin A plays an important role in desmosome-mediated cell-cell adhesion in the lower levels of the epidermis.
Peeling Skin Syndrome 4
In a consanguineous Bedouin kindred in which 5 individuals had peeling skin of the hands and feet as well as generalized dry scaling skin over the remainder of the body (PSS4; 607936), which mapped to chromosome 3q21, Blaydon et al. (2011) identified homozygosity for a splice site mutation in the candidate gene CSTA (184600.0001) that segregated with disease in the family and was not detected in 300 control chromosomes. In affected members of a Turkish family with a similar phenotype of exfoliative ichthyosis, Blaydon et al. (2011) identified homozygosity for a nonsense mutation in CSTA (184600.0002).
In affected members of a large Jordanian American family with an acral form of peeling skin syndrome, Krunic et al. (2013) identified a homozygous nonsense mutation in the CSTA gene (K22X; 184600.0003).
In a 25-year-old Iranian man with generalized peeling skin and diffuse palmoplantar hyperkeratosis, Moosbrugger-Martinz et al. (2015) identified homozygosity for a nonsense mutation in the CSTA gene (R58X; 184600.0004).
Associations Pending Confirmation
See 604316 for discussion of a possible association between variation in the CSTA gene and psoriasis.
See 603165 for discussion of a possible association between variation in the CSTA gene and atopic dermatitis.
In affected members of a consanguineous Bedouin kindred with exfoliative ichthyosis (PSS4; 607936), originally studied by Hatsell et al. (2003), Blaydon et al. (2011) identified homozygosity for an A-to-T transversion in intron 1 (67-2A-T) of the CSTA gene. The mutation segregated with disease in the family and was not found in 300 control chromosomes.
In affected members of a Turkish family with exfoliative ichthyosis (PSS4; 607936), Blaydon et al. (2011) identified homozygosity for a 256C-T transition in the CSTA gene, resulting in a gln86-to-ter (Q86X) substitution at a highly conserved residue within the conserved cystatin domain.
In affected members of a consanguineous Jordanian American family with an acral form of peeling skin syndrome (PSS4; 607936), originally described by Pavlovic et al. (2012), Krunic et al. (2013) identified homozygosity for a c.64A-T transversion (c.64A-T, NM_005213) in exon 1 of the CSTA gene, resulting in a lys22-to-ter (K22X) substitution. The mutation, which segregated with disease in the family, was not found in approximately 500 in-house control exomes or in the 1000 Genomes Project database.
In a 25-old Iranian man with generalized peeling skin and diffuse palmoplantar hyperkeratosis (PSS4; 607936), Moosbrugger-Martinz et al. (2015) identified homozygosity for a c.172C-T transition in exon 3 of the CSTA gene, resulting in an arg58-to-ter (R58X) substitution. The mutation was reported as an extremely rare variant (rs149474339) in the NHLBI Exome Sequencing project, with 1 heterozygous c.172C-T allele detected among 13,005 chromosomes from European and African American individuals (minor allele frequency, 0.0077%). Immunostaining of patient skin showed complete absence of cystatin A in all epidermal layers.
Blaydon, D. C., Nitoiu, D., Eckl, K.-M., Cabral, R. M., Bland, P., Hausser, I., van Heel, D. A., Rajpopat, S., Fischer, J., Oji, V., Zvulunov, A., Traupe, H., Hennies, H. C., Kelsell, D. P. Mutations in CSTA, encoding cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion. Am. J. Hum. Genet. 89: 564-571, 2011. [PubMed: 21944047] [Full Text: https://doi.org/10.1016/j.ajhg.2011.09.001]
Hatsell, S. J., Stevens, H., Jackson, A. P., Kelsell, D. P., Zvulunov, A. An autosomal recessive exfoliative ichthyosis with linkage to chromosome 12q13. Brit. J. Derm. 149: 174-180, 2003. [PubMed: 12890214] [Full Text: https://doi.org/10.1046/j.1365-2133.2003.05386.x]
Hsieh, W.-T., Fong, D., Sloane, B. F., Golembieski, W., Smith, D. I. Mapping of the gene for human cysteine proteinase inhibitor stefin A, STF1, to chromosome 3cen-q21. Genomics 9: 207-209, 1991. [PubMed: 2004763] [Full Text: https://doi.org/10.1016/0888-7543(91)90241-6]
Krunic, A. L., Stone, K. L., Simpson, M. A., McGrath, J. A. Acral peeling skin syndrome resulting from a homozygous nonsense mutation in the CSTA gene encoding cystatin A. Pediat. Derm. 30: e87-e88, 2013. Note: Electronic Article. [PubMed: 23534700] [Full Text: https://doi.org/10.1111/pde.12092]
Moosbrugger-Martinz, V., Jalili, A., Schossig, A. S., Jahn-Bassler, K., Zschocke, J., Schmuth, M., Stingl, G., Eckl, K. M., Hennies, H. C., Gruber, R. Epidermal barrier abnormalities in exfoliative ichthyosis with a novel homozygous loss-of-function mutation in CSTA. Brit. J. Derm. 172: 1628-1632, 2015. [PubMed: 25400170] [Full Text: https://doi.org/10.1111/bjd.13545]
Pavlovic, S., Krunic, A. L., Bulj, T. K., Medenica, M. M., Fong, K., Arita, K., McGrath, J. A. Acral peeling skin syndrome: a clinically and genetically heterogeneous disorder. Pediat. Derm. 29: 258-263, 2012. [PubMed: 22066523] [Full Text: https://doi.org/10.1111/j.1525-1470.2011.01563.x]
Strauss, M., Stollwerk, J., Lenarcic, B., Turk, V., Jany, K.-D., Gassen, H. G. Chemical synthesis of a gene for human stefin A and its expression in E. coli. Biol. Chem. Hoppe Seyler 369: 1019-1030, 1988. [PubMed: 3067731] [Full Text: https://doi.org/10.1515/bchm3.1988.369.2.1019]
Takahashi, H., Asano, K., Kinouchi, M., Ishida-Yamamoto, A., Wueppers, K. D., Iizuka, H. Structure and transcriptional regulation of the human cystatin A gene: the 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element-2 site (-272 to -278) on cystatin A gene is critical for TPA-dependent regulation. J. Biol. Chem. 273: 17375-17380, 1998. [PubMed: 9651321] [Full Text: https://doi.org/10.1074/jbc.273.28.17375]
Takahashi, M., Tezuka, T., Katunuma, N. Phosphorylated cystatin-alpha is a natural substrate of epidermal transglutaminase for formation of skin cornified envelope. FEBS Lett. 308: 79-82, 1992. [PubMed: 1353732] [Full Text: https://doi.org/10.1016/0014-5793(92)81055-q]
Tsui, F. W. L., Tsui, H.-W., Mok, S., Mlinaric, I., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Siminovitch, K. A. Molecular characterization and mapping of murine genes encoding three members of the stefin family of cysteine proteinase inhibitors. Genomics 15: 507-514, 1993. [PubMed: 8468045] [Full Text: https://doi.org/10.1006/geno.1993.1101]