Alternative titles; symbols
HGNC Approved Gene Symbol: DLAT
Cytogenetic location: 11q23.1 Genomic coordinates (GRCh38) : 11:112,025,408-112,064,404 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.1 | Pyruvate dehydrogenase E2 deficiency | 245348 | Autosomal recessive | 3 |
The DLAT gene encodes dihydrolipoamide acetyltransferase (EC 2.3.1.12), the E2 subunit of the mammalian pyruvate dehydrogenase complex (PDC; EC 1.2.4.1) of the inner mitochondrial membrane. Patients with primary biliary cirrhosis (PBC; 109720) show autoantibodies to DLAT.
Thekkumkara et al. (1987) cloned cDNAs encoding DLAT, which they called PDCE2, from a human liver expression library. Thekkumkara et al. (1988) assembled and sequenced the cDNAs. The deduced 615-amino acid PDCE2 protein contains an N-terminal 54-amino acid leader sequence, followed by a lipoyl-bearing domain with 2 lipoyl-binding sites; a central dihydrolipoamide dehydrogenase (DLD; 238331)-binding site; a hinge region; and a C-terminal catalytic domain. The mature 561-amino acid protein has a calculated molecular mass of 59.6 kD. Human PDCE2 shares significant similarity with Pdce2 from bovine heart and rat liver. Northern blot analysis detected 4.0-, 2.9-, and 2.3-kb transcripts in human heart total RNA.
Coppel et al. (1988) cloned DLAT by screening a placenta cDNA library with rat Dlat. The deduced protein contains 614 amino acids and has a calculated molecular mass of 65.6 kD. The signal peptide shows characteristics of a mitochondrial targeting sequence. Rat and human DLAT share 86% amino acid identity. Northern blot analysis of 3 human cell lines detected several transcripts of 1.8 to 3.2 kb. Transcripts of 2.7, 2.9, and 3.2 kb were most prominent.
Moehario et al. (1990) cloned 2 partial PDCE2 cDNAs by screening a heart cDNA library with rat Dlat. The cDNAs differed slightly from the cDNA cloned from a placenta library by Coppel et al. (1988), suggesting that tissue-specific isoforms of the PDCE2 protein may exist.
By FISH, Leung et al. (1993) mapped the DLAT gene to chromosome 11q23.1.
In 2 unrelated patients with pyruvate dehydrogenase E2 deficiency (PDHDD; 245348), Head et al. (2005) identified different homozygous mutations in the DLAT gene (c.361del3, 608770.0001 and F576L, 608770.0002).
In a patient with PDHDD and paroxysmal exercise-induced dyskinesia, who was born to consanguineous Iraqi parents, Friedman et al. (2017) identified a homozygous mutation in the DLAT gene (V157G; 608770.0003).
In a patient with pyruvate dehydrogenase E2 deficiency (PDHDD; 245348), who was born of first-cousin parents, Head et al. (2005) identified a homozygous 3-bp deletion in exon 2 of the DLAT gene, resulting in the deletion of glu121 in the outer of the 2 lipoyl domains of the enzyme, toward the N-terminal end. Pyruvate dehydrogenase complex activity was severely decreased in the patient, whereas both parents had intermediate activity. The patient showed neurologic dysfunction in infancy and responded well to dietary treatment.
In a patient with pyruvate dehydrogenase E2 deficiency (PDHDD; 245348), who was born of first-cousin parents, Head et al. (2005) identified a homozygous c.1728C-A transversion in exon 13 of the DLAT gene, resulting in a phe576-to-leu (F576L) substitution at a highly conserved residue within the catalytic site of the enzyme. Structural analysis and mutagenesis studies indicated that residue phe576 is important in determining substrate specificity.
In a patient with pyruvate dehydrogenase E2 deficiency (PDHDD; 245348) and paroxysmal exercise-induced dyskinesia, who was born to consanguineous Iraqi parents, Friedman et al. (2017) identified a homozygous c.470T-G transversion in the DLAT gene, resulting in a val157-to-gly (V157G) substitution at a highly conserved residue. The mutation was also found in the patient's sister, who had similar findings on a limited evaluation.
Coppel, R. L., McNeilage, L. J., Surh, C. D., Van de Water, J., Spithill, T. W., Whittingham, S., Gershwin, M. E. Primary structure of the human M2 mitochondrial autoantigen of primary biliary cirrhosis: dihydrolipoamide acetyltransferase. Proc. Nat. Acad. Sci. 85: 7317-7321, 1988. [PubMed: 3174635] [Full Text: https://doi.org/10.1073/pnas.85.19.7317]
Friedman, J., Feigenbaum, A., Chuang, N., Silhavy, J., Gleeson, J. G. Pyruvate dehydrogenase complex-E2 deficiency causes paroxysmal exercise-induced dyskinesia. Neurology 89: 2297-2298, 2017. [PubMed: 29093066] [Full Text: https://doi.org/10.1212/WNL.0000000000004689]
Head, R. A., Brown, R. M., Zolkipli, Z., Shahdadpuri, R., King, M. D., Clayton, P. T., Brown, G. K. Clinical and genetic spectrum of pyruvate dehydrogenase deficiency: dihydrolipoamide acetyltransferase (E2) deficiency. Ann. Neurol. 58: 234-241, 2005. [PubMed: 16049940] [Full Text: https://doi.org/10.1002/ana.20550]
Leung, P. S. C., Watanabe, Y., Munoz, S., Teuber, S. S., Patel, M. S., Korenberg, J. R., Hara, P., Coppel, R., Gershwin, M. E. Chromosome localization and RFLP analysis of PDC-E2: the major autoantigen of primary biliary cirrhosis. Autoimmunity 14: 335-340, 1993. [PubMed: 8102256] [Full Text: https://doi.org/10.3109/08916939309079237]
Moehario, L. H., Smooker, P. M., Devenish, R. J., Mackay, I. R., Gershwin, M. E., Marzuki, S. Nucleotide sequence of a cDNA encoding the lipoate acetyl transferase (E2) of human heart pyruvate dehydrogenase complex differs from that of human placenta. Biochem. Int. 20: 417-422, 1990. [PubMed: 2317220]
Thekkumkara, T. J., Ho, L., Wexler, I. D., Pons, G., Liu, T.-C., Patel, M. S. Nucleotide sequence of a cDNA for the dihydrolipoamide acetyltransferase component of human pyruvate dehydrogenase complex. FEBS Lett. 240: 45-48, 1988. [PubMed: 3191998] [Full Text: https://doi.org/10.1016/0014-5793(88)80337-5]
Thekkumkara, T. J., Jesse, B. W., Ho, L., Raefsky, C., Pepin, R. A., Javed, A. A., Pons, G., Patel, M. S. Isolation of a cDNA clone for the dihydrolipoamide acetyltransferase component of the human liver pyruvate dehydrogenase complex. Biochem. Biophys. Res. Commun. 145: 903-907, 1987. [PubMed: 3036145] [Full Text: https://doi.org/10.1016/0006-291x(87)91050-3]