Alternative titles; symbols
HGNC Approved Gene Symbol: LDHB
Cytogenetic location: 12p12.1 Genomic coordinates (GRCh38): 12:21,635,342-21,657,842 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p12.1 | [Lactate dehydrogenase-B deficiency] | 614128 | 3 |
The LDHB gene encodes the B subunit of lactate dehydrogenase (EC 1.1.1.27), an enzyme that catalyzes the interconversion of lactate and pyruvate (summary by Markert, 1984).
Sakai et al. (1987) isolated and sequenced LDHB cDNA. The deduced LDHB protein contains 333 amino acids. Nucleotide and amino acid sequences for the LDHB enzyme showed 68% and 75% identity, respectively, with those of LDHA (150000).
Takeno and Li (1989) determined that the LDHB gene contains 7 coding exons.
LDHB and peptidase B (169900) are linked (Santachiara et al., 1970) and both loci are on chromosome 12 (Chen et al., 1973). In a case of deletion of the short arm of chromosome 12, Weiss et al. (1973) found evidence that LDHB is located there.
From study of somatic cell hybrids Hamerton et al. (1975) concluded that LDHB is in the 12pter-q21 region. Rethore et al. (1975) found augmentation of LDHB activity in a boy trisomic for the short arm of chromosome 12. From study of 3 patients with different deletions of chromosome 12, Rethore et al. (1976) concluded that the G3PD locus (138400) is on the distal part of 12p and that the LDHB locus is on the middle third between 12p12.1 and 12p12.2.
Steinbach and Rehder (1987) demonstrated dosage effect with LDHB in a case of tetrasomy of 12p.
Pseudogenes
Sudo et al. (1990) demonstrated 93% homology between an LDHB processed pseudogene and the functional gene. The pseudogene was mapped to the X chromosome by dot-blot analysis.
The LDHB AND LDHA (150000) subunits generate 5 tetrameric isozymes. Although all LDH isozymes catalyze the interconversion of pyruvate and lactate, they do so with different kinetics. The B subunits in heart muscle are bound to NAD. Heart muscle B4 isozymes function principally to oxidize lactic acid to pyruvate with the generation of NADH which, in turn, is oxidized through the cytochrome system to generate energy to support the normal physiology of the heart. Through a negative feedback system involving LDHB, a constant ratio of NAD to NADH is maintained (summary by Markert, 1984).
Mohrenweiser and Neel (1981) identified thermolabile variants of lactate dehydrogenase B, glucosephosphate isomerase, and glucose-6-phosphate dehydrogenase. None was detectable as a variant by standard electrophoretic techniques. All were inherited.
In a clinically normal 43-year-old male who was found to have low LDH activity in serum by Houki et al. (1986), Sudo et al. (1990) identified a homozygous mutation in the LDHB gene (150100.0001). LDHB mutations have been found in other individuals with LDHB deficiency (see, e.g., 150100.0002-150100.0004).
Okumura et al. (1999) tabulated the LDHB variants caused by missense mutations.
Houki et al. (1986) described a clinically normal 43-year-old man who was found to have low LDH activity (614128) in the serum during health examinations. Findings on electrophoresis suggested the synthesis of unstable LDHB subunits in vivo. In the man reported by Houki et al. (1986), Sudo et al. (1990) demonstrated an A-to-G substitution in exon 4, causing a substitution of histidine for arginine at residue 173; the arginine coded by CGC is a highly conserved residue which is involved in an anion-binding site at the P-axis of LDH subunits. Sudo et al. (1992) demonstrated that the subject was homozygous for the arg173-to-his mutation.
In a 44-year-old clinically normal male who had low serum LDH activity (614128), Sudo et al. (1992) identified homozygosity for an A-to-C transversion in exon 3 of the LDHB gene, resulting in ser131-to-arg substitution. Two of his children were heterozygous for the mutation.
Maekawa et al. (1993) described the mutational basis of an electrophoretically fast LDHB variant found in a 65-year-old male with diabetes mellitus and slightly decreased LDH activity (614128). An A-to-G transition, which changed codon 6 from AAA to GAA, resulted in the replacement of a lysine by a glutamic acid (K6E). The change may result in heat instability and affect the net charge of the variant subunit.
Okumura et al. (1999) described homozygosity and heterozygosity for a trp323-to-arg mutation in LDHB in individuals with lactate dehydrogenase B deficiency (614128). They designated the homozygous and heterozygous types as Matsumoto I and Matsumoto II, respectively. The substitution of the positively charged arg residue for an uncharged trp residue was consistent with a decrease in net negative charge (slow-type) of the variant LDHB subunit observed by isoenzyme analysis. The 2 subjects were not known to be related. The homozygote was a 58-year-old woman with coronary artery disease; the heterozygote was a 35-year-old healthy man.
Boyer, S. H., Fainer, D. C., Watson-Williams, E. J. Lactate dehydrogenase variant from human blood: evidence for molecular subunits. Science 141: 642-643, 1963. [PubMed: 14014718] [Full Text: https://doi.org/10.1126/science.141.3581.642]
Chen, T.-R., McMorris, F. A., Creagan, R., Ricciuti, F. C., Tischfield, J., Ruddle, F. H. Assignment of the genes for malate oxidoreductase decarboxylating to chromosome 6 and peptidase B and lactate dehydrogenase B to chromosome 12 in man. Am. J. Hum. Genet. 25: 200-207, 1973. [PubMed: 4689040]
Hamerton, J. L., Mohandas, T., McAlpine, P. J., Douglas, G. R. Localization of human gene loci using spontaneous chromosome rearrangements in human-Chinese hamster somatic cell hybrids. Am. J. Hum. Genet. 27: 595-608, 1975. [PubMed: 1172370]
Herbschleb-Voogt, E., Meera Khan, P. Defining the locus of origin of a genetically determined electrophoretic variant of a multilocus enzyme system; the Calcutta-1 of human LDH system is a B-locus variant. Hum. Genet. 57: 290-295, 1981. [PubMed: 7250971] [Full Text: https://doi.org/10.1007/BF00278947]
Houki, N., Matsushima, Y., Kitamura, M., Tukada, T., Nishina, T., Nakayama, T. A case of deficiency of lactate dehydrogenase H-subunit. Jpn. J. Clin. Chem. 15: 85-90, 1986.
Maekawa, M., Sudo, K., Kitajima, M., Matsuura, Y., Li, S. S.-L., Kanno, T. Analysis of a genetic mutation in an electrophoretic variant of the human lactate dehydrogenase-B(H) subunit. Hum. Genet. 91: 423-426, 1993. [PubMed: 8314553] [Full Text: https://doi.org/10.1007/BF00217765]
Malpuech, G., Kaplan, J. C., Rethore, M. O., Junien, C., Geneix, A. Une observation de deletion partielle du bras court du chromosome 12: localisation du gene de la lacticodeshydrogenase B. Lyon Med. 233: 275-279, 1975.
Markert, C. L. Lactate dehydrogenase: biochemistry and function of lactate dehydrogenase. Cell Biochem. Funct. 2: 131-134, 1984. [PubMed: 6383647] [Full Text: https://doi.org/10.1002/cbf.290020302]
Mayeda, K., Weiss, L., Lindahl, R., Dully, M. Localization of the human lactate dehydrogenase B gene on the short arm of chromosome 12. Am. J. Hum. Genet. 26: 59-64, 1974. [PubMed: 4811755]
Mohrenweiser, H. W., Neel, J. V. Frequency of thermostability variants: estimation of total 'rare' variant frequency in human populations. Proc. Nat. Acad. Sci. 78: 5729-5733, 1981. [PubMed: 6946512] [Full Text: https://doi.org/10.1073/pnas.78.9.5729]
Okumura, N., Terasawa, F., Ueno, I., Oki, K., Yamauchi, K., Hidaka, H., Tozuka, M., Okura, M., Katsuyama, T. Genetic analyses in homozygous and heterozygous variants of lactate dehydrogenase-B (H) subunit: LD-B Matsumoto I and II (LD-B W323R). Clin. Chim. Acta 287: 163-171, 1999. [PubMed: 10509905] [Full Text: https://doi.org/10.1016/s0009-8981(99)00127-8]
Rethore, M.-O., Junien, C., Malpuech, G., Baccichetti, C., Tenconi, R., Kaplan, J. C., de Romeuf, J., Lejeune, J. Localisation du gene de la glyceraldehyde 3-phosphate dehydrogenase (G3PD) sur le segment distal du bras court du chromosome 12. Ann. Genet. 19: 140-142, 1976. [PubMed: 1085604]
Rethore, M.-O., Kaplan, J.-C., Junien, C., Cruveiller, J., Dutrillaux, B., Aurias, A., Carpentier, S., Lafourcade, J., Lejeune, J. Augmentation de l'activite de la LDH-B chez un garcon trisomique 12p par malsegregation d'une translocation maternelle t(12;14)(q12;p11). Ann. Genet. 18: 81-87, 1975. [PubMed: 1081369]
Sakai, I., Sharief, F. S., Pan, Y.-C. E., Li, S. S.-L. The cDNA and protein sequences of human lactate dehydrogenase B. Biochem. J. 248: 933-936, 1987. [PubMed: 3435492] [Full Text: https://doi.org/10.1042/bj2480933]
Santachiara, A. S., Nabholz, M., Miggiano, V., Darlington, A. J., Bodmer, W. F. Linkage between human lactate dehydrogenase B and peptidase B genes. Nature 227: 248-251, 1970. [PubMed: 5428190] [Full Text: https://doi.org/10.1038/227248a0]
Steinbach, P., Rehder, H. Tetrasomy for the short arm of chromosome 12 with accessory isochromosome (+i[12p]) and a marked LDH-B gene dosage effect. Clin. Genet. 32: 1-4, 1987. [PubMed: 3476222] [Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb03314.x]
Sudo, K., Maekawa, M., Ikawa, S., Machida, K., Kitamura, M., Li, S. S.-L. A missense mutation found in human lactate dehydrogenase-B (H) variant gene. Biochem. Biophys. Res. Commun. 168: 672-676, 1990. [PubMed: 2334429] [Full Text: https://doi.org/10.1016/0006-291x(90)92373-8]
Sudo, K., Maekawa, M., Luedemann, M. M., Deaven, L. L., Li, S. S.-L. Human lactate dehydrogenase-B processed pseudogene: nucleotide sequence analysis and assignment to the X-chromosome. Biochem. Biophys. Res. Commun. 171: 67-74, 1990. [PubMed: 2393406] [Full Text: https://doi.org/10.1016/0006-291x(90)91357-x]
Sudo, K., Maekawa, M., Tomonaga, A., Tsukada, T., Nakayama, T., Kitamura, M., Li, S. S.-L., Kanno, T., Toriumi, J. Molecular characterization of genetic mutations in human lactate dehydrogenase (LDH)B (H) variant. Hum. Genet. 89: 158-162, 1992. [PubMed: 1587525] [Full Text: https://doi.org/10.1007/BF00217116]
Takeno, T., Li, S. S.-L. Structure of the human lactate dehydrogenase B gene. Biochem. J. 257: 921-924, 1989. [PubMed: 2930497] [Full Text: https://doi.org/10.1042/bj2570921]
Van Someren, H., Meera Khan, P., Westerveld, A., Bootsma, D. Human genetics--two new linkage groups carrying different loci for LDH and glutamic-pyruvic transaminase found. Nature 240: 221-222, 1972.
Weiss, L., Mayeda, K., Lindahl, R., Dully, M. Localization of human LDH-B gene of the short arm of chromosome 12. (Abstract) Am. J. Hum. Genet. 25: 85A only, 1973.