Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINB6
Cytogenetic location: 6p25.2 Genomic coordinates (GRCh38) : 6:2,948,159-2,971,793 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p25.2 | ?Deafness, autosomal recessive 91 | 613453 | Autosomal recessive | 3 |
Coughlin et al. (1993) described a cDNA encoding a serine proteinase inhibitor present in placental tissue and in the cytosolic fraction of the leukemic cell line K562. On the basis of its interaction with thrombin, through which it was discovered, the inhibitor was operationally named the placental thrombin inhibitor (PTI). Amino acid sequence comparisons suggested that its reactive center is located at arg341 and cys342, that it lacks a classic N-terminal signal sequence, and that it has the highest degree of similarity to intracellular serine proteinase inhibitors (serpins), such as the human monocyte/neutrophil elastase inhibitor (ELANH2; 130135). Analysis of human tissue mRNA indicated that PTI is expressed widely, with the highest levels in cardiac and skeletal muscle and placenta. Coughlin et al. (1993) concluded that PTI is a member of an emerging class of intracellular serpins.
Sun et al. (1995) showed that expression of the mouse PI6 homolog, Spi3, is developmentally regulated, and that, unlike the situation in the human, Spi3 is absent from the mouse placenta.
Nishibori et al. (1995) isolated a serum protease, designated B43, from bovine brain. They used histochemical staining to demonstrate its presence in fibrous astroglial cells, particularly in endfeet-like cellular structures, suggesting its involvement in the blood-brain barrier. Partial amino acid sequence of the protease suggested that it was the homolog of human PI6 and mouse Spi3.
Sun et al. (1995) determined that the mouse Spi3 gene spans 20 kb, contains 7 exons and 6 introns, and contains a TATA motif 24 bp upstream of the transcriptional start site.
Coughlin et al. (1995) used fluorescence in situ hybridization to map the SERPINB6 gene to chromosome 6p25.
While studying a cluster of serine proteinase inhibitors of the ovalbumin family, including maspin (SERPINB6; 154790) located on chromosome 18q21.3, Schneider et al. (1995) prepared PCR primer sets for the 3-prime untranslated region of PTI. Using the NIGMS monochromosomal somatic cell hybrid panel, they mapped the PTI gene to chromosome 6. Evans et al. (1995) confirmed the assignment to chromosome 6 and regionalized it to 6pter-p24 by demonstrating that PI6 colocalizes with another Ov-serpin gene, ELANH2 (130135). The localization was achieved with a chromosome 6 regional hybrid DNA panel.
Sun et al. (1995) mapped the mouse Spi3 gene to chromosome 13 between the Pl1 and ctla2a genes.
Sirmaci et al. (2010) found that Serpinb6 was expressed in crista hair cells of the mouse inner ear at embryonic day (E) 16.5. Hair cell expression was sustained in adult mice. Serpinb6 was expressed in the cytoplasm of both cochlear and utricular hair cells in the embryo and early postnatal age, and in the greater epithelial ridge region in early postnatal age.
By genomewide linkage analysis followed by candidate gene sequencing in affected members of a consanguineous Turkish family with nonsyndromic progressive hearing loss (DFNB91; 613453), Sirmaci et al. (2010) identified a homozygous truncating mutation in the SERPINB6 gene (E245X; 173321.0001), resulting in loss of function. Sirmaci et al. (2010) concluded that SERPINB6 plays an important role in the inner ear in the protection against leakage of lysosomal content during stress, and that loss of this protection results in cell death and sensorineural hearing loss.
Shearer et al. (2014) stated that they had identified a partial deletion in the SERPINB6 gene as a cause of autosomal recessive nonsyndromic hearing loss (their table 1), but provided no additional information.
Scarff et al. (2004) found that Spi3-deficient mice developed normally, were fertile, and had no obvious pathology. Increased levels of Elanh2 in the tissues of mutant mice suggested that compensation by other serpins reduced the impact of Spi3 deficiency.
Tan et al. (2013) noted that mice express multiple related clade B serpins that have no human counterparts and that mouse Serpinb6a is the ortholog of human SERPINB6. They found that homozygous replacement of Serpinb6a with green fluorescent protein had no effect on cochlear or vestibular development but caused progressive hearing loss, concomitant with cochlear degeneration, after 2 weeks of age. The effect first appeared as loss of outer hair cells before spreading to inner hair cells and primary auditory neurons and, finally, to types 1, 2, and 4 fibrocytes. Since loss of Serpinb6a expression had no effect on cochlear development, Tan et al. (2013) hypothesized that Serpinb6a expression is required for cochlear homeostasis.
In affected members of a consanguineous Turkish family with nonsyndromic progressive hearing loss (DFNB91; 613453), Sirmaci et al. (2010) identified a homozygous 744G-T transversion in the SERPINB6 gene, resulting in a gly245-to-ter (E245X) substitution, which removes 131 amino acids in the C-terminal region that includes the reactive center loop. Further studies showed that the mutation resulted in mRNA decay and complete lack of protein expression. The mutation was not found in 300 Turkish controls or in an additional 542 Turkish, Greek, American, and Palestinian families, mostly with congenital hearing loss. In vitro functional expression studies in HeLa cells showed that the E245X mutation resulted in increased loss of lysosomal integrity in response to osmotic shock compared to cells transfected with wildtype SERPINB6. These findings suggested that wildtype SERPINB6 is required to counter potentially cytotoxic components of leaking lysosomal proteases that result from various stress conditions. Although the precise age of onset could not be ascertained, the youngest affected individual, who was 23 years old, reported loss of hearing after age 20. The hearing loss was progressive and age-dependent, consistent with a loss of function of an intracellular protease inhibitor.
Coughlin, P., Nicholl, J., Sun, J., Salem, H., Bird, P., Sutherland, G. R. Chromosomal mapping of the human proteinase inhibitor 6 (PI6) gene to 6p25 by fluorescence in situ hybridization. Genomics 26: 431-433, 1995. [PubMed: 7601482] [Full Text: https://doi.org/10.1016/0888-7543(95)80240-m]
Coughlin, P., Sun, J., Cerruti, L., Salem, H. H., Bird, P. Cloning and molecular characterization of a human intracellular serine proteinase inhibitor. Proc. Nat. Acad. Sci. 90: 9417-9421, 1993. [PubMed: 8415716] [Full Text: https://doi.org/10.1073/pnas.90.20.9417]
Evans, E., Cooley, J., Remold-O'Donnell, E. Characterization and chromosomal localization of ELANH2, the gene encoding human monocyte/neutrophil elastase inhibitor. Genomics 28: 235-240, 1995. [PubMed: 8530031] [Full Text: https://doi.org/10.1006/geno.1995.1136]
Nishibori, M., Ohtsuka, A., Kawabata, M., Nakaya, N., Murakami, T., Saeki, K. A novel serpin-like protein, B-43, exists in both neurons and astrocytes: an immunohistochemical study in the parietal region of the bovine brain. Neurosci. Lett. 200: 125-128, 1995. [PubMed: 8614560] [Full Text: https://doi.org/10.1016/0304-3940(95)12095-l]
Scarff, K. L., Ung, K. S., Nandurkar, H., Crack, P. J., Bird, C. H., Bird, P. I. Targeted disruption of SPI3/Serpinb6 does not result in developmental or growth defects, leukocyte dysfunction, or susceptibility to stroke. Molec. Cell. Biol. 24: 4075-4082, 2004. [PubMed: 15082799] [Full Text: https://doi.org/10.1128/MCB.24.9.4075-4082.2004]
Schneider, S. S., Schick, C., Fish, K. E., Miller, E., Pena, J. C., Treter, S. D., Hui, S. M., Silverman, G. A. A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc. Nat. Acad. Sci. 92: 3147-3151, 1995. [PubMed: 7724531] [Full Text: https://doi.org/10.1073/pnas.92.8.3147]
Shearer, A. E., Kolbe, D. L., Azaiez, H., Sloan, C. M., Frees, K. L., Weaver, A. E., Clark, E. T., Nishimura, C. J., Black-Ziegelbein, E. A., Smith, R. J. H. Copy number variants are a common cause of non-syndromic hearing loss. Genome Med. 6: 37, 2014. Note: Electronic Article. [PubMed: 24963352] [Full Text: https://doi.org/10.1186/gm554]
Sirmaci, A., Erbek, S., Price, J., Huang, M., Duman, D., Cengiz, F. B., Bademci, G., Tokgoz-Yilmaz, S., Hismi, B., Ozdag, H., Ozturk, B., Kulaksizoglu, S., and 13 others. A truncating mutation in SERPINB6 is associated with autosomal-recessive nonsyndromic sensorineural hearing loss. Am. J. Hum. Genet. 86: 797-804, 2010. [PubMed: 20451170] [Full Text: https://doi.org/10.1016/j.ajhg.2010.04.004]
Sun, J., Rose, J. B., Bird, P. Gene structure, chromosomal localization, and expression of the murine homologue of human proteinase inhibitor 6 (PI-6) suggests divergence of PI-6 from the ovalbumin serpins. J. Biol. Chem. 270: 16089-16096, 1995. [PubMed: 7608171] [Full Text: https://doi.org/10.1074/jbc.270.27.16089]
Tan, J., Prakash, M. D., Kaiserman, D., Bird, P. I. Absence of SERPINB6A causes sensorineural hearing loss with multiple histopathologies in the mouse inner ear. Am. J. Path. 183: 49-59, 2013. [PubMed: 23669344] [Full Text: https://doi.org/10.1016/j.ajpath.2013.03.009]