Alternative titles; symbols
HGNC Approved Gene Symbol: LDHA
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:18,394,563-18,408,425 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.1 | Glycogen storage disease XI | 612933 | Autosomal recessive | 3 |
The LDHA gene encodes the A subunit of lactate dehydrogenase (EC 1.1.1.27), an enzyme that catalyzes the interconversion of lactate and pyruvate. The A subunit is expressed in skeletal muscle. Other isoforms include LDHB (150100), expressed in cardiac muscle, and LDHC (150150), expressed in testis (Tsujibo et al., 1985; Chung et al., 1985).
Tsujibo et al. (1985) isolated cDNA clones corresponding to the human LDHA gene from a human fibroblast cDNA library. The predicted 332-amino acid sequence had a molecular mass of 36.7 kD and showed 92% homology to the porcine Ldha polypeptide. A nonfunctional pseudogene was also isolated.
Chung et al. (1985) determined that the LDHA gene contains 7 exons and spans about 12 kb.
Studies using human-mouse somatic cell hybrids indicated that the LDHA and LDHB loci are not linked (Nabholz et al., 1969). By study of cell hybrids, LDHA was assigned to the short arm of chromosome 11 by Francke and Busby (1975).
By the study of cells from 4 persons with different interstitial deletions of 11p, Francke et al. (1977) assigned the LDHA locus to 11p1203-11p1208. At HGM8, controversy arose over the mapping of LDHA (see Grzeschik and Kazazian, 1985). HGM8 reported the location as 11p14-p12. Lebo et al. (1985) and Lewis et al. (1985) placed the locus at a more distal position.
Yang-Feng et al. (1986) did in situ hybridization studies in cell lines from 2 persons with apparently balanced translocations involving 11p13. Their findings excluded LDHA from any region proximal to 11p13 and localized the gene to 11p15-p14.
Scrable et al. (1990) demonstrated that LDHA is located in band 11p15.4.
Centrosomal proteins (e.g., 117139, 117140, 117141, 117143) have been studied mainly with anticentrosome serum. Using a spontaneously arising rabbit anticentrosome serum with strong human specificity, Gosti et al. (1987) identified specific antigens in isolated centrosomes which reacted with several noncentrosomal proteins, notably, lactate dehydrogenase.
Anderson and Kovacik (1981) identified an unusual isozyme of lactate dehydrogenase, which they designated lactate dehydrogenase K (LDHK), in cells transformed by the Kirsten murine sarcoma virus. They examined 16 different human carcinomas and found that 11 had LDHK activity 10- to 500-fold over the level in adjoining nontumor tissue. Li et al. (1988) determined that this cancer-associated lactate dehydrogenase is a tyrosylphosphorylated form of LDHA. The protein was found to be complexed with 21-kD, 30-kD, and 56-kD proteins.
Aerobic glycolysis is a metabolic hallmark of activated T cells and has been implicated in augmenting effector T-cell responses, including expression of interferon-gamma (IFNG; 147570), via 3-prime UTR-mediated mechanisms. Peng et al. (2016) found that Ldha, but not Ldhb, was induced upon activation of mouse T cells. Deletion of Ldha specifically in mouse Cd4 (186940)-positive T cells resulted in little to no lactate production, indicating a loss of aerobic glycolysis, in naive and activated T cells. Ldha deficiency did not affect development in thymus, but it led to diminished Ifng production. Ifng production depended on Ldha maintaining high concentrations of acetyl coenzyme A to enhance histone acetylation and transcription of Ifng, independently of its 3-prime UTR. Ldha ablation in T cells protected mice from immunopathology triggered by excess Ifng expression or by deficiency of regulatory T cells. Peng et al. (2016) concluded that aerobic glycolysis promotes effector T-cell differentiation via an epigenetic rather than a translational mechanism.
Nance et al. (1963) observed a genetically determined variant LDH in the red cells of 4 members of 2 generations of a Brazilian family. The mutation involved the A subunit. This was the first instance in which practical considerations permitted demonstration of the variant in multiple relatives. Unlike the findings of Shaw and Barto (1963) in Peromyscus and of Boyer et al. (1963) in man, the findings in the Brazilian family did not suggest random association between the products of the mutant and wildtype alleles.
LDH variants, involving either the A or the B subunit, seem to be unusually frequent in India (Das et al., 1970).
Glycogen Storage Disease XI
In a patient with LDHA deficiency, or glycogen storage disease XI (GSD11; 612933), reported by Maekawa et al. (1986), Maekawa et al. (1990) found homozygosity for a 20-bp deletion in exon 6 of the LDHA gene (150000.0001). Maekawa et al. (1991) demonstrated the same mutation in 18 persons from the 4 known affected families in Japan.
Markert et al. (1975) suggested that the ancestral vertebrate LDH was an A4-like enzyme since lampreys have only the A4 isozyme. Sidell and Beland (1980) presented evidence supporting this view: the hagfish has a B4 enzyme but it diverges less from A4 enzyme than does the B4 of other fishes and higher vertebrates. A close phylogenic relative of the lamprey, the Atlantic hagfish lives under sustained hypoxic conditions that may have favored evolution of a B4 enzyme. A4 is the muscle isozyme, B4 is the heart isozyme, and C4 is the testicular isozyme.
Morizot (1984) collated linkage data from lower vertebrates and several mammalian species. The lower vertebrates included poeciliid fishes (Xiphophorus and Poeciliopsis), salmonid fishes (trout), and frogs (Rana). He postulated a 12-locus ancestral synteny group consisting of isocitrate dehydrogenase (on human 2 and 15), 3 LDH loci (on human 11 and 12), HEXA (on human 15), nucleoside phosphorylase (on human 14), pyruvate kinase (on human 15), MPI (on human 15), PEPB (on human 12), citrate synthase (on human 12), TPI (on human 12), and glyceraldehyde-3-phosphate dehydrogenase (on human 12). If the 3 LDH loci are part of the primordial synteny group, LDH genes may have originated by intrachromosomal duplication rather than by polyploidization as has been thought.
In trout, the loci coding for LDH subunits A and B are linked (Morrison and Wright, 1966). In the mouse, Chang et al. (1979) found that the A and B subunits are more similar to each other in amino acid sequence than to the C subunit.
In the mouse, Merkle et al. (1992) found that homozygosity for absent LDHA subunit led to early postimplantation death. Merkle et al. (1992) suggested that the fact that human subjects with a complete absence of LDHA subunits are fully viable may be due to the fact that, in contrast with the situation in the mouse, LDHB predominates in the human fetus.
In a patient with lactate dehydrogenase A deficiency, or glycogen storage disease XI (GSD11; 612933), reported by Maekawa et al. (1986), Maekawa et al. (1990) found a 20-bp deletion in exon 6 of the LDHA gene, resulting in a frameshift, premature termination, and complete lack of the alpha subunits of LDH. The predicted incomplete LDHA subunit contained only 259 instead of 331 amino acids and appeared to be degraded rapidly, since no protein was detected immunologically. Maekawa et al. (1990) stated that 'this female patient with the LDHA deficiency frequently complained of uterine stiffness during her pregnancy. Uterine stiffness was a problem in the early stage of delivery and, thus, she required a Caesarean section.'
In a fragment of the LDHA gene amplified by PCR using 2 primers specific for the gene, Maekawa et al. (1991) demonstrated the same mutation in 18 persons from the 4 known affected families in Japan.
Miyajima et al. (1993) identified the exon 6 deletion in 2 adult Japanese sisters who had muscle stiffness following strenuous exercise since the teens and age 9, respectively. Both had had cesarean sections because the 'uterus was too stiff in the early stage of delivery.'
This variant, formerly titled GLYCOGEN STORAGE DISEASE XI, has been reclassified as a variant of unknown significance because its association with the disorder has not been confirmed.
Maekawa et al. (1991) used the ratio of LDHB to LDHA subunits in erythrocytes as a means of identifying individuals heterozygous for LDHA deficiency (GSD11; 612933). In one such individual, they identified a G-to-T transversion in the LDHA gene, resulting in a glu328-to-ter (E328X) substitution. There were no manifestations in this heterozygous subject; however, homozygotes would presumably be affected.
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Yang-Feng, T. L., Bruns, G. A. P., Carroll, A. J., Simola, K. O. J., Francke, U. Localization of the LDHA gene to 11p14-11p15 by in situ hybridization of an LDHA cDNA probe to two translocations with breakpoints in 11p13. Hum. Genet. 74: 331-334, 1986. [PubMed: 3793094] [Full Text: https://doi.org/10.1007/BF00280481]