Alternative titles; symbols
HGNC Approved Gene Symbol: BLMH
Cytogenetic location: 17q11.2 Genomic coordinates (GRCh38): 17:30,248,203-30,291,944 (from NCBI)
The gene encoding bleomycin hydrolase (BMH) was cloned and found to encode a 455-amino acid protein containing the signature active site residues of the cysteine protease papain superfamily (Bromme et al., 1996; Ferrando et al., 1996). The protein had aminopeptidase activity that was blocked by the irreversible cysteine protease inhibitor E-64. Ferrando et al. (1996) found the BMH protein to be approximately 40% identical to that of the yeast homolog Gal6. Both yeast and human BMH also possess endopeptidase activity. The gene is expressed in many human tissues with elevated expression levels found in testis, skeletal muscle, and pancreas, and low levels of expression in colon and peripheral blood leukocytes (Bromme et al., 1996).
Montoya et al. (1997) mapped the BLMH gene to chromosome 17 using a human/rodent hybrid mapping panel and localized it to 17q11.1-q11.2 by linkage analysis using the CEPH reference database. By fluorescence in situ hybridization, Ferrando et al. (1997) mapped the BLMH gene to 17q11.2, very close to the locus of the NF1 gene (613113).
Montoya et al. (1997) found that the BLMH gene contains 11 exons ranging in size from 69 to 198 bp separated by introns of approximately 1 kb, reflecting the archetypal genomic structure of the cysteine protease family. Ferrando et al. (1997) concluded that BLMH contains 12 coding exons and spans more than 30 kb. They also concluded that the number and distribution of exons and introns differ from those reported for other human cysteine proteinases, indicating that these genes are only distantly related. The nuclear sequence of the 5-prime flanking region of the gene had characteristics of housekeeping genes, consistent with the widespread expression of bleomycin hydrolase in human tissues. The 5-prime flanking region of the gene also contains a polymorphic CCG trinucleotide repeat that may be a target of genetic instability events and affect its transcriptional activity.
Bleomycin hydrolase is highly conserved through evolution; however, the only known activity of the enzyme is metabolic inactivation of the glycopeptide bleomycin (BLM), a component of combination chemotherapy regimens for cancer. Even in low doses, bleomycin has the unfortunate property of inducing pulmonary toxicity in approximately 3 to 5% of patients; cumulative doses greater than 450 mg induced potentially lethal pulmonary toxicity in up to 10% of patients. Lazo and Humphreys (1983) considered the BMH gene to be a primary candidate for protection against potential fatal bleomycin-induced pulmonary fibrosis and bleomycin resistance in tumors. Haston et al. (1996) presented evidence for a genetic basis for susceptibility to BMH-induced pulmonary fibrosis.
The yeast Gal6 protein forms a barrel structure with the active sites embedded in a channel as in the proteasome. The C termini lie in the active site clefts. Zheng et al. (1998) showed that Gal6 acts as a carboxypeptidase on its C terminus to convert itself to an aminopeptidase and peptide ligase. The substrate specificity of the peptidase activity is determined by the position of the C terminus of Gal6 rather than the sequence of the substrate. The authors proposed a model to explain these diverse activities and the ability of yeast Gal6 to inactivate bleomycin.
Southern blot analysis of DNA from leukocytes and autologous breast tumors showed that the bleomycin hydrolase gene is not a frequent target of amplification in human breast carcinomas (Ferrando et al., 1997).
Susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes may reflect the way a person deals with carcinogenic challenges (Hsu et al., 1989). This susceptibility, also referred to as mutagen sensitivity (see 610452), has been found to be increased in patients with environmentally related cancers, including cancers of the head and neck, lung, and colon. In combination with carcinogenic exposure, this susceptibility can greatly influence cancer risk.
Using PCR-SSCP, Bromme et al. (1996) and Montoya et al. (1997) found a 1450A-G polymorphism of the BMH gene that resulted in an ile443-to-val (I443V) conserved amino acid substitution in the carboxy terminus of the protein (602403.0001). BMH is suspected of being the unknown beta secretase that cleaves off the amyloid beta fragment from the amyloid precursor protein (APP; 104760) associated with Alzheimer disease (AD). In pooled AD cases and controls, the frequency of the 1450A and 1450G alleles were statistically indistinguishable. The G/G homozygote genotype distribution, however, was significantly different between AD cases (12.7%) and controls (6.6%); (P less than 0.001). Significant differences were not seen in the A/A homozygote and A/G heterozygote genotype distributions. Further studies by Montoya et al. (1998) indicated that the frequency of the G/G homozygote was significantly higher in AD cases than in controls only in the non-APOE4 (see 107741) group (15.9% in cases vs 4.7% in controls). The odds ratio for developing AD with BMH G/G genotype in the absence of an APOE4 allele was 3.81; in the presence of an APOE4 allele, the odds ratio was 0.98. Farrer et al. (1998) were unable to confirm this association in a sample of 621 Caucasian Alzheimer patients drawn from 4 North American university-based research centers.
In mouse strains differing in susceptibility to bleomycin-induced lung fibrosis, Haston et al. (2002) showed highly significant linkage to only 2 loci. The first locus, on chromosome 17 in the major histocompatibility complex (MHC) (lod = 17.4), named BLM-induced pulmonary fibrosis-1 (Blmpf1), was highly significant in both males and females, and accounted for approximately 20% of the phenotypic variance. The authors confirmed the presence of Blmpf1 in MHC congenic mice and narrowed the region to 2.7 cM in a reduced MHC congenic strain. The second locus, on chromosome 11 (lod = 5.6) (Blmpf2), was significant in males only. Functional studies demonstrated that bleomycin hydrolase activity modulated bleomycin-induced pulmonary fibrosis, suggesting that it may be a candidate gene for Blmpf2. The authors suggested sex-specific models of susceptibility to bleomycin-induced lung fibrosis, with an interaction between Blmpf2 and Blmpf1 for the more susceptible males and Blmpf1 as the major locus in females.
Polymorphism in the bleomycin hydrolase gene in the form of a 1450A-G nucleotide change resulting in an ile443-to-val amino acid substitution was identified in the carboxy terminus of the bleomycin hydrolase gene by Bromme et al. (1996). As indicated earlier, an increased frequency of G/G homozygotes was found among non-APOE4 cases of Alzheimer disease (see 104300).
Bromme, D., Rossi, A. B., Smeekens, S. P., Anderson, D. C., Payan, D. G. Human bleomycin hydrolase: molecular cloning, sequencing, functional expression, and enzymatic characterization. Biochemistry 35: 6706-6714, 1996. [PubMed: 8639621] [Full Text: https://doi.org/10.1021/bi960092y]
Farrer, L. A., Abraham, C. R., Haines, J. L., Rogaeva, E. A., Song, Y., McGraw, W. T., Brindle, N., Premkumar, S., Scott, W. K., Yamaoka, L. H., Saunders, A. M., Roses, A. D., Auerbach, S. A., Sorbi, S., Duara, R., Pericak-Vance, M. A., St. George-Hyslop, P. H. Association between bleomycin hydrolase and Alzheimer's disease in Caucasians. Ann. Neurol. 44: 808-811, 1998. [PubMed: 9818937] [Full Text: https://doi.org/10.1002/ana.410440515]
Ferrando, A. A., Pendas, A. M., Llano, E., Velasco, G., Lidereau, R., Lopez-Otin, C. Gene characterization, promoter analysis, and chromosomal localization of human bleomycin hydrolase. J. Biol. Chem. 272: 33298-33304, 1997. [PubMed: 9407121] [Full Text: https://doi.org/10.1074/jbc.272.52.33298]
Ferrando, A. A., Velasco, G., Campo, E., Lopez-Otin, C. Cloning and expression analysis of human bleomycin hydrolase, a cysteine proteinase involved in chemotherapy resistance. Cancer Res. 56: 1746-1750, 1996. [PubMed: 8620487]
Haston, C. K., Amos, C. I., King, T. M., Travis, E. L. Inheritance of susceptibility to bleomycin-induced pulmonary fibrosis in the mouse. Cancer Res. 56: 2596-2601, 1996. [PubMed: 8653703]
Haston, C. K., Wang, M., Dejournett, R. E., Zhou, X., Ni, D., Gu, X., King, T. M., Weil, M. M., Newman, R. A., Amos, C. I., Travis, E. L. Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice. Hum. Molec. Genet. 11: 1855-1863, 2002. [PubMed: 12140188] [Full Text: https://doi.org/10.1093/hmg/11.16.1855]
Hsu, T. C., Johnston, D. A., Cherry, L. M., Ramkissoon, D., Schantz, S. P., Jessup, J. M., Winn, R. J., Shirley, L., Furlong, C. Sensitivity to genotoxic effects of bleomycin in humans: possible relationship to environmental carcinogenesis. Int. J. Cancer 43: 403-409, 1989. [PubMed: 2466800] [Full Text: https://doi.org/10.1002/ijc.2910430310]
Lazo, J. S., Humphreys, C. J. Lack of metabolism as the biochemical basis of bleomycin-induced pulmonary toxicity. Proc. Nat. Acad. Sci. 80: 3064-3068, 1983. [PubMed: 6190169] [Full Text: https://doi.org/10.1073/pnas.80.10.3064]
Montoya, S. E., Aston, C. E., DeKosky, S. T., Kamboh, M. I., Lazo, J. S., Ferrell, R. E. Bleomycin hydrolase is associated with risk of sporadic Alzheimer's disease. (Letter) Nature Genet. 18: 211-212, 1998. Note: Erratum: Nature Genet. 19: 404 only, 1998. [PubMed: 9500538] [Full Text: https://doi.org/10.1038/ng0398-211]
Montoya, S. E., Ferrell, R. E., Lazo, J. S. Genomic structure and genetic mapping of the human neutral cysteine protease bleomycin hydrolase. Cancer Res. 57: 4191-4195, 1997. [PubMed: 9331073]
Zheng, W., Johnston, S. A., Joshua-Tor, L. The unusual active site of Gal6/bleomycin hydrolase can act as a carboxypeptidase, aminopeptidase, and peptide ligase. Cell 93: 103-109, 1998. [PubMed: 9546396] [Full Text: https://doi.org/10.1016/s0092-8674(00)81150-2]