Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINB7
SNOMEDCT: 722205008;
Cytogenetic location: 18q21.33 Genomic coordinates (GRCh38): 18:63,753,057-63,805,370 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.33 | Palmoplantar keratoderma, Nagashima type | 615598 | Autosomal recessive | 3 |
Tsujimoto et al. (1997) purified a new member of the serine protease inhibitor (serpin) superfamily with megakaryocyte maturation activity. Using RACE and PCR, they cloned SERPINB7 cDNA, which encodes a 380-amino acid protein that has 38% sequence identity to the serpin plasminogen activator inhibitor type 2 (173390).
Mesangial cells play an important role in maintaining the structure and function of the glomerulus and in the pathogenesis of glomerular diseases. To identify a specific gene expressed in human mesangial cells, Miyata et al. (1998) used rapid large-scale DNA sequencing and computerized data processing to compare the transcripts in cultured human mesangial cells with various different cells and organs. Using this novel approach, they discovered a mesangium-predominant gene, which they termed 'megsin.' The protein encoded by this gene was identical to that isolated by Tsujimoto et al. (1997). The amino acid sequences in the reactive loop site of megsin showed characteristic features of functional serpins. Northern blot and RT-PCR analyses of various tissues and cells demonstrated that megsin is predominantly expressed in human mesangial cells.
By immunostaining, Kubo et al. (2013) demonstrated the expression of SERPINB7 in the stratum corneum and granulosum of palmoplantar as well as facial and abdominal human skin, suggesting that SERPINB7 is expressed in the epidermis of the whole body.
McDonough et al. (2009) stated that the SERPINB7 gene maps to chromosome 18q21.33.
Using in situ hybridization, Miyata et al. (1998) showed megsin expression in the mesangium of normal glomeruli and increased expression in the expanded mesangium of glomeruli from patients with IgA nephropathy in parallel with the degree of mesangial proliferation.
Nagashima-Type Palmoplantar Keratoderma
In 13 unrelated Japanese patients with the Nagashima type of palmoplantar keratoderma (PPKN; 615598), Kubo et al. (2013) identified homozygosity or compound heterozygosity for 3 different truncating mutations in the SERPINB7 gene (603357.0001-603357.0003). Noting that SERPINB7 was originally described as being expressed in kidney mesangial cells, Kubo et al. (2013) stated that no renal manifestations were identified in any of the PPKN patients.
In 7 sporadic Chinese patients with PPKN, Yin et al. (2014) identified homozygosity or compound heterozygosity for mutations in the SERPINB7 gene (see, e.g., R266X, 603357.0001 and 603357.0004). The recurrent R266X mutation was present in homozygosity in 4 patients and in compound heterozygosity with another mutation in 2; SNP analysis suggested that these 6 patients shared a common mutant haplotype, indicating that R266X likely represents a founder mutation rather than a mutation hotspot.
In affected members of 10 Japanese families with PPKN, Mizuno et al. (2014) identified homozygosity or compound heterozygosity for SERPINB7 mutations (see, e.g., 603357.0001-603357.0003). All of the patients carried R266X on at least 1 allele.
Associations Pending Confirmation
For discussion of a possible association between variation in the SERPINB7 gene and diabetic nephropathy in African Americans, see MVCD1 (603933).
To elucidate the role of megsin in mesangial function, Miyata et al. (2002) produced 2 lines of transgenic mice with overexpression of megsin. The mice developed progressive mesangial matrix expression, an increase in the number of mesangial cells, and an augmented immune complex deposition, together with immunoglobulins and complement. Binding and functional assays in vitro identified plasmin as a biologic substrate of megsin and confirmed the activity of megsin as a proteinase inhibitor. Transgenic mice exhibiting nephritis as a result of treatment with antiglomerular basement membrane antiserum showed significantly more persistent expansion of the mesangial extracellular matrix than was seen in control mice.
Takano et al. (2006) found that transgenic rats with overexpression of megsin (Tgmeg) in multiple cell types developed a phenotype similar to that of familial encephalopathy with neuroserpin inclusion bodies (FENIB; 604218), a human neurodegenerative disorder caused by mutations in the neuroserpin gene (PI12; 602445). Homozygous Tgmeg rats developed PAS-positive, diastase-resistant intracellular droplets in the kidneys and pancreas that was accompanied by marked upregulation of endoplasmic reticulum (ER) stress chaperones. Homozygous Tgmeg rats displayed early and progressive organ damage, but heterozygotes failed to show abnormalities in either renal or endocrine function. Although heterozygotes had a similar life span compared to nontransgenic littermates, they developed PAS-positive intracellular inclusion in neurons of the cerebral cortex, hippocampus, and substantia nigra, associated with slowly progressive neurodegeneration, upregulation of ER-stress proteins, and neuronal death. Takano et al. (2006) proposed that ER stress may have a pathogenic role in the development of serpinopathy, ultimately leading to neurodegeneration.
In 6 unrelated Japanese patients with the Nagashima type of palmoplantar keratoderma (PPKN; 615598), Kubo et al. (2013) identified homozygosity for a c.796C-T transition in exon 8 of the SERPINB7 gene, resulting in an arg266-to-ter (R266X) substitution. Seven more unrelated Japanese PPKN patients were compound heterozygous for R266X and another truncating mutation in SERPINB7: the second mutation in 5 of the patients was a 2-bp deletion/12-bp insertion (c.218_219delAGinsTAAACTTTACCT; 603357.0002) at the end of exon 3, causing a frameshift predicted to result in a premature stop codon (Gln73LeufsTer17); the second mutation in the remaining 2 patients was a splice site mutation (c.455-1G-A; 603357.0003) in intron 5, also predicted to result in a premature stop codon (Gly152ValfsTer21). In the 9 sets of unaffected parents available for study, each was heterozygous for 1 of the mutations. The R266X variant was identified as a SNP (rs142859678) in the 1000 Genomes Project database with a minor allele frequency of 0.4%. R266X was present in heterozygosity in 2 of 89 Japanese individuals, 4 of 97 Han Chinese individuals from Beijing, and 2 of 100 Han Chinese individuals from southern China, but was not found in any of 806 non-Asian individuals, suggesting that R266X is a founder mutation causing PPKN in Asian populations.
In 4 unrelated Chinese patients with PPKN, Yin et al. (2014) identified homozygosity for the R266X mutation in the SERPINB7 gene; R266X was present in compound heterozygosity with another truncating mutation in 2 additional PPKN patients. All 10 available parents were unaffected heterozygous carriers of the respective mutations. SNP analysis suggested that the 6 patients shared a common mutant haplotype, indicating that R266X likely represents a founder mutation rather than a mutation hotspot.
In 4 Japanese families with PPKN, including 1 with a pseudodominant pattern of inheritance, Mizuno et al. (2014) identified homozygosity for the R266X mutation. In 6 additional families, affected individuals were compound heterozygous for R266X and another mutation in the SERPINB7 gene: in 3 families, the second mutation was the previously identified 2-bp deletion/12-bp insertion (603357.0002), whereas in another 2 families, the second allele carried the previously identified splice site mutation in IVS5 (603357.0003). In 1 family, the second mutation was a different splice site mutation, c.336+3T-G, which was not found in 50 ethnically matched controls.
For discussion of the 2-bp deletion/12-bp insertion in the SERPINB7 gene that was found in compound heterozygous state in patients with the Nagashima type of palmoplantar keratoderma (PPKN; 615598) by Kubo et al. (2013) and Mizuno et al. (2014), see 603357.0001.
For discussion of the splice site mutation in the SERPINB7 gene that was found in compound heterozygous state in patients with the Nagashima type of palmoplantar keratoderma (PPKN; 615598) by Kubo et al. (2013) and Mizuno et al. (2014), see 603357.0001.
In a 30-year-old Chinese man who developed the Nagashima type of palmoplantar keratoderma (PPKN; 615598) at 4 years of age, Yin et al. (2014) identified homozygosity for a 1-bp insertion (c.522insT) in the SERPINB7 gene, causing a frameshift predicted to result in premature termination (Val175CysfsTer46) with loss of the entire reactive-site loop motif. His unaffected parents were heterozygous for the mutation. Additional features in the patient included onychomycosis, tinea pedis, and hyperhidrosis.
Kubo, A., Shiohama, A., Sasaki, T., Nakabayashi, K., Kawasaki, H., Atsugi, T., Sato, S., Shimizu, A., Mikami, S., Tanizaki, H., Uchiyama, M., Maeda, T., and 15 others. Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis. Am. J. Hum. Genet. 93: 945-956, 2013. [PubMed: 24207119] [Full Text: https://doi.org/10.1016/j.ajhg.2013.09.015]
McDonough, C. W., Bostrom, M. A., Lu, L., Hicks, P. J., Langefeld, C. D., Divers, J., Mychaleckyj, J. C., Freedman, B. I., Bowden, D. W. Genetic analysis of diabetic nephropathy on chromosome 18 in African Americans: linkage analysis and dense SNP mapping. Hum. Genet. 126: 805-817, 2009. [PubMed: 19690890] [Full Text: https://doi.org/10.1007/s00439-009-0732-8]
Miyata, T., Inagi, R., Nangaku, M., Imasawa, T., Sato, M., Izuhara, Y., Suzuki, D., Yoshino, A., Onogi, H., Kimura, M., Sugiyama, S., Kurokawa, K. Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion. J. Clin. Invest. 109: 585-593, 2002. [PubMed: 11877466] [Full Text: https://doi.org/10.1172/JCI14336]
Miyata, T., Nangaku, M., Suzuki, D., Inagi, R., Uragami, K., Sakai, H., Okubo, K., Kurokawa, K. A mesangium-predominant gene, megsin, is a new serpin upregulated in IgA nephropathy. J. Clin. Invest. 102: 828-836, 1998. [PubMed: 9710452] [Full Text: https://doi.org/10.1172/JCI2450]
Mizuno, O., Nomura, T., Suzuki, S., Takeda, M., Ohguchi, Y., Fujita, Y., Nishie, W., Sugiura, K., Akiyama, M., Shimizu, H. Highly prevalent SERPINB7 founder mutation causes pseudodominant inheritance pattern in Nagashima-type palmoplantar keratosis. Brit. J. Derm. 171: 847-853, 2014. [PubMed: 24773080] [Full Text: https://doi.org/10.1111/bjd.13076]
Takano, K., Kitao, Y., Inagi, R., Momoi, T., Matsuyama, T., Miyata, T., Yoneda, Y., Iso, H., Stern, D. M., Hori, O., Ogawa, S. A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies). Biochem. Biophys. Res. Commun. 346: 1040-1047, 2006. [PubMed: 16782060] [Full Text: https://doi.org/10.1016/j.bbrc.2006.06.016]
Tsujimoto, M., Tsuruoka, N., Ishida, N., Kurihara, T., Iwasa, F., Yamashiro, K., Rogi, T., Kodama, S., Katsuragi, N., Adachi, M., Katayama, T., Nakao, M., Yamaichi, K., Hashino, J., Haruyama, M., Miura, K., Nakanishi, T., Nakazato, H., Teramura, M., Mizoguchi, H., Yamaguchi, N. Purification, cDNA cloning, and characterization of a new serpin with megakaryocyte maturation activity. J. Biol. Chem. 272: 15373-15380, 1997. [PubMed: 9182567] [Full Text: https://doi.org/10.1074/jbc.272.24.15373]
Yin, J., Xu, G., Wang, H., Zhao, J., Duo, L., Cao, X., Tang, Z., Lin, Z., Yang, Y. New and recurrent SERPINB7 mutations in seven Chinese patients with Nagashima-type palmoplantar keratosis. (Letter) J. Invest. Derm. 134: 2269-2272, 2014. [PubMed: 24514002] [Full Text: https://doi.org/10.1038/jid.2014.80]