Alternative titles; symbols
HGNC Approved Gene Symbol: PDHB
Cytogenetic location: 3p14.3 Genomic coordinates (GRCh38): 3:58,427,630-58,433,832 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p14.3 | Pyruvate dehydrogenase E1-beta deficiency | 614111 | Autosomal recessive | 3 |
Pyruvate dehydrogenase is a tetramer consisting of 2 alpha subunits (PDHA1; 300502) and 2 beta subunits (PDHB). The enzyme, which is found in mitochondria, is one of the component enzymes of the pyruvate dehydrogenase multienzyme complex (PDH). It catalyzes the first reaction of an oxidative decarboxylation sequence converting pyruvate to acetyl-CoA and CO(2) (summary by Koike et al., 1988).
Koike et al. (1988) cloned and sequenced cDNAs encoding the alpha and the beta subunits.
Ho et al. (1988) isolated a 1.5-kb cDNA clone for the beta subunit of E1 from a human liver gamma-gt11 cDNA library using anti-E1 serum.
Using a cDNA probe, Olson et al. (1990) demonstrated that the PHE1B gene is located on 3p13-q23.
Gross (2018) mapped the PDHB gene to chromosome 3p14.3 based on an alignment of the PDHB sequence (GenBank BC000439) with the genomic sequence (GRCh38).
Koike et al. (1990) described the molecular cloning of the entire human PHE1B gene, its characterization by restriction enzyme analysis, and its complete nucleotide sequence. The PHE1B gene contains 10 exons. All intron-exon splice junctions follow the GT/AG rule. The Alu family was found in introns 2 and 8.
In 2 unrelated patients with pyruvate dehydrogenase deficiency (PDHBD; 614111), Brown et al. (2004) identified homozygous missense mutations in the PDHB gene (Y132C, 179060.0001; P344S, 179060.0002). The patients presented with lactic acidosis and neurologic dysfunction and had little residual PDH activity in cultured fibroblasts. The consequences of the mutations could be analyzed by comparison with the normal structure of the human PDH E1 enzyme.
In 4 unrelated patients with PDHBD, Okajima et al. (2008) identified homozygous or compound heterozygous missense mutations in the PDHB gene (179060.0003-179060.0007). Fibroblasts from the patients showed reduced PDC activity compared to controls. Molecular modeling predicted enzyme instability and disruption of PDH alpha/beta and beta/beta interactions.
In 2 unrelated patients with PDHBD, Quintana et al. (2009) identified homozygous or compound heterozygous missense mutations in the PDHB gene (179060.0008-179060.0010). The mutations were identified by gene sequencing and were located at conserved residues. Based on protein localization and changes in amino acid polarity or charge of the mutated residues, Quintana et al. (2009) hypothesized that the mutations modified the interactions between the alpha and beta chains and destabilized the PDH E1 enzyme. The hypothesis was supported by decreased E1-alpha and E1-beta expression compared to E2 (608770) expression in patient fibroblasts and muscle tissue.
In 2 sib fetuses with PDHBD, Pirot et al. (2016) identified a homozygous missense mutation (L104V; 179060.0011) in the PDHB gene that segregated with the disorder in the family.
In an infant with pyruvate dehydrogenase deficiency (PDHBD; 614111), the son of first-cousin parents, Brown et al. (2004) identified a homozygous c.395A-G transition in exon 6 of the PDHB gene, resulting in a tyr132-to-cys (Y132C) substitution.
In an affected 13-month-old sib (patient D) of the patient reported by Brown et al. (2004), Okajima et al. (2008) identified homozygosity for the Y132C mutation by direct gene sequencing. The parents were shown to be heterozygous for the mutation. Molecular modeling predicted that the Y132C mutation may lead to PDH tetramer instability and may affect interactions between the PDH alpha and beta subunits. Immunoblotting against PDH E1 in patient fibroblast homogenates showed a reduction of both PDH E1-alpha and PDH-E1 beta content compared to controls. Fibroblast PDC activity was reduced in patient fibroblasts and lymphocytes compared to controls.
In an infant with pyruvate dehydrogenase deficiency (PDHBD; 614111), the son of consanguineous parents, Brown et al. (2004) identified a c.1030C-T transition in exon 10 of the PDHB gene, resulting in a pro344-to-ser (P344S) substitution.
In a 6.5-year-old Iraqi boy (patient A), born of consanguineous parents, with pyruvate dehydrogenase E1-beta deficiency (PDHBD; 614111), Okajima et al. (2008) identified homozygosity for a c.106C-T transition in exon 3 of the PDHB gene, resulting in an arg36-to-cys (R36C) substitution. The mutation, which was identified by direct gene sequencing and confirmed by restriction enzyme digestion analysis, segregated with the disorder in the family. Fibroblast PDC activity was 6% of control levels in patient-derived fibroblasts and lymphocytes. Immunoblotting against PDH E1 in patient fibroblast homogenates showed a slightly larger PDH E1-beta band size, with no change in signal intensity compared to controls. Molecular modeling predicted that the R36C mutation may disrupt structurally important hydrogen bonds that hold the first alpha helix of the PDH E1-beta subunit in position.
In an infant (patient B) with pyruvate dehydrogenase E1-beta deficiency (PDHBD; 614111), Okajima et al. (2008) identified compound heterozygous mutations in the PDHB gene: a c.916T-C transition in exon 9, resulting in a cys306-to-arg (C306R) substitution, and a c.956A-T transversion in exon 10, resulting in an asp319-to-val (D319V; 179060.0005) substitution. The mutations were identified by direct gene sequencing. Each parent was heterozygous for one of the mutations. Okajima et al. (2008) found that fibroblasts from the patient had 3% of PDC activity compared to controls. Molecular modeling predicted that the C306R mutation may disrupt interaction between the 2 beta subunits and destabilize the PDH E1 tetramer, and that the D319V mutation may have an effect on PDH E1-E2 binding. Okajima et al. (2008) suggested that these 2 mutations may act synergistically because they are located near each other in the PDH E1 tetramer.
For discussion of the c.956A-T transversion in the PDHB gene, resulting in an asp319-to-val (D319V) substitution, that was found in compound heterozygous state in a patient with pyruvate dehydrogenase E1-beta deficiency (PDHBD; 614111) by Okajima et al. (2008), see 179060.0004.
In a 26-year-old patient (patient C) with pyruvate dehydrogenase E1-beta deficiency (PDHBD; 614111), Okajima et al. (2008) identified compound heterozygous mutations in exon 6 of the PDHB gene: a c.426A-G transition, resulting in an ile142-to-met (I142M) substitution, and a c.494G-C transversion, resulting in a trp165-to-ser (W165S; 179060.0007) substitution. The mutations were identified by direct gene sequencing. Parental samples were not available for mutation testing. Fibroblasts from the patient had 27% of PDC activity compared to controls. Molecular modeling predicted that the I142M mutation may disturb the conformation of E1-beta and potassium binding, and that the W165S mutation may weaken the interaction between the 2 beta subunits.
For discussion of the c.494G-C transversion in the PDHB gene, resulting in a trp165-to-ser (W165S) substitution, that was found in compound heterozygous state in a patient with pyruvate dehydrogenase E1-beta deficiency (PDHBD; 614111) by Okajima et al. (2008), see 179060.0006.
In a patient (patient 1) with pyruvate dehydrogenase E1-beta deficiency (PDHBD; 614111), who was born to consanguineous parents, Quintana et al. (2009) identified homozygosity for a c.302T-C transition (c.302T-C, NM_000925) in exon 5 of the PDHB gene, resulting in a met101-to-thr (M101T) substitution at a conserved residue. The mutations, which were identified by direct gene sequencing, segregated with the disorder in the family. Among 200 control chromosomes, the M101T mutation was identified once. Western blot analysis in patient fibroblasts showed decreased E1-alpha and E1-beta PDH subunit protein content compared to controls. PDC and individual PDH E1 enzyme activity were also reduced in patient fibroblasts compared to controls.
In a patient (patient 2) with pyruvate dehydrogenase E1-beta deficiency (PDHBD; 614111), Quintana et al. (2009) identified compound heterozygous mutations in the PDHB gene: a c.301A-G transition (c.301A-G, NM_000925) in exon 5, resulting in a met101-to-val substitution (M101V) at a conserved residue, and a c.313G-A transition, resulting in an arg105-to-gln (R105Q; 179060.0010) substitution. The mutations, which were identified by direct gene sequencing, segregated with the disorder in the family. Neither mutation was identified in 200 control chromosomes. PDC activity in muscle tissue was reduced compared to controls, but was normal in fibroblasts.
For discussion of the c.313G-A transition (c.313G-A, NM_000925) in the PDHB gene, resulting in an arg105-to-gln (R105Q) substitution, that was found in a compound heterozygous state in a patient with pyruvate dehydrogenase E1-beta deficiency (PDHBD; 614111) by Quintana et al. (2009), see 179060.0009.
In 2 sib fetuses with pyruvate dehydrogenase E1-beta deficiency (PDHBD; 614111), Pirot et al. (2016) identified a homozygous c.310T-G transversion (c.310T-G, NM_00095) in the PDHB gene, resulting in a leu104-to-val (L104V) substitution. The mutation segregated with the disorder in the family.
Brown, R. M., Head, R. A., Boubriak, I. I., Leonard, J. V., Thomas, N. H., Brown, G. K. Mutations in the gene for the E1-beta subunit: a novel cause of pyruvate dehydrogenase deficiency. Hum. Genet. 115: 123-127, 2004. [PubMed: 15138885] [Full Text: https://doi.org/10.1007/s00439-004-1124-8]
Gross, M. B. Personal Communication. Baltimore, Md. 3/9/2018.
Ho, L., Javed, A. A., Pepin, R. A., Thekkumkara, T. J., Raefsky, C., Mole, J. E., Caliendo, A. M., Kwon, M. S., Kerr, D. S., Patel, M. S. Identification of a cDNA clone for the beta-subunit of the pyruvate dehydrogenase component of human pyruvate dehydrogenase complex. Biochem. Biophys. Res. Commun. 150: 904-908, 1988. [PubMed: 2829898] [Full Text: https://doi.org/10.1016/0006-291x(88)90714-0]
Koike, K., Ohta, S., Urata, Y., Kagawa, Y., Koike, M. Cloning and sequencing of cDNAs encoding alpha and beta subunits of human pyruvate dehydrogenase. Proc. Nat. Acad. Sci. 85: 41-45, 1988. [PubMed: 3422424] [Full Text: https://doi.org/10.1073/pnas.85.1.41]
Koike, K., Urata, Y., Koike, M. Molecular cloning and characterization of human pyruvate dehydrogenase beta subunit gene. Proc. Nat. Acad. Sci. 87: 5594-5597, 1990. [PubMed: 2377599] [Full Text: https://doi.org/10.1073/pnas.87.15.5594]
Okajima, K., Korotchkina, L. G., Prasad, C., Rupar, T., Phillips, J. A., III, Ficicioglu, C., Hertecant, J., Patel, M. S., Kerr, D. S. Mutations of the E1-beta subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency. Molec. Genet. Metab. 93: 371-380, 2008. [PubMed: 18164639] [Full Text: https://doi.org/10.1016/j.ymgme.2007.10.135]
Olson, S., Song, B. J., Huh, T.-L., Chi, Y.-T., Veech, R. L., McBride, O. W. Three genes for enzymes of the pyruvate dehydrogenase complex map to human chromosomes 3, 7, and X. Am. J. Hum. Genet. 46: 340-349, 1990. Note: Erratum: Am. J. Hum. Genet. 46: 1235 only, 1990. [PubMed: 1967901]
Pirot, N., Crahes, M., Adle-Biassette, H., Soares, A., Bucourt, M., Boutron, A., Carbillon, L., Mignot, C., Trestard, L., Bekri, S., Laquerriere, A. Phenotypic and neuropathological characterization of fetal pyruvate dehydrogenase deficiency. J. Neuropath. Exp. Neurol. 75: 227-238, 2016. [PubMed: 26865159] [Full Text: https://doi.org/10.1093/jnen/nlv022]
Quintana, E., Mayr, J. A., Garcia Silva, M. T., Font, A., Tortoledo, M. A., Moliner, S., Ozaez, L., Lluch, M., Cabello, A., Ricoy, J. R., Koch, J., Ribes, A., Sperl, W., Briones, P. PDH E1-beta deficiency with novel mutations in two patients with Leigh syndrome. J. Inherit. Metab. Dis. 32 (Suppl. 1): S339-S343, 2009. [PubMed: 19924563] [Full Text: https://doi.org/10.1007/s10545-009-1343-1]