Alternative titles; symbols
HGNC Approved Gene Symbol: DLST
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38): 14:74,881,916-74,903,743 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.3 | Pheochromocytoma/paraganglioma syndrome 7 | 618475 | Autosomal dominant | 3 |
The DLST gene encodes dihydrolipoamide succinyltransferase, which is a component of the structural core of the alpha-keto glutarate (alpha-KG) dehydrogenase complex in the citric acid cycle (TCA). The alpha-keto acid dehydrogenase complexes (pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex, and branched chain alpha-keto acid dehydrogenase complex) are a family of multienzyme complexes. They are localized in mitochondria and catalyze the oxidative decarboxylation of alpha-keto acids. These 3 alpha-keto acid dehydrogenase complexes are composed of 3 different enzymes: alpha-keto acid dehydrogenase (E1; 300502), dihydrolipoamide acyltransferase (E2), and dihydrolipoamide dehydrogenase (E3; 238331) (summary by Nakano et al., 1993).
Nakano et al. (1993) isolated a cDNA corresponding to DLST from a human fibroblast cDNA library. Amino acid sequence analysis supported their previous observation (Nakano et al., 1993) that human dihydrolipoamide succinyltransferase lacks a sequence motif for an E1 and/or E3 binding site. By Northern blot analysis, Ali et al. (1994) detected ubiquitous expression of DLST in peripheral tissues and brain.
Nakano et al. (1993) found that the DLST gene contains 3 exons and 4 introns and that the nucleotide sequence at the 5-prime donor and 3-prime acceptor sites of all introns conformed to the gt-ag rule.
DLST is the E2 component of the alpha-ketoglutarate dehydrogenase complex. In contrast to the E2 components of the other 2 alpha-keto acid dehydrogenase complexes, the pyruvate dehydrogenase complex (see 300502) and the branched-chain alpha-keto acid dehydrogenase complex (see 608348), the alpha-KGDC E2 has a unique structure consisting of 2 domains and lacking a sequence motif of an E3 and/or E1 binding site (Patel and Harris, 1995).
By fluorescence in situ hybridization, Nakano et al. (1993) found that the DLST gene is located on 14q24.2-q24.3 and that a related sequence is located on 1p31. The gene for the dihydrolipoamide acyltransferase of the branched chain alpha-keto acid dehydrogenase complex (DBT; 248610), the site of the mutation in type 2 maple syrup urine disease (see 248600), is located on 1p31. Nakano et al. (1993) mentioned the possibility that mutation of the DLST gene may be a cause of familial Alzheimer disease that maps to 14q24.3 (AD3; 607822). Ali et al. (1994) mapped the DLST gene (symbolized by them KGDHC) to 14q24.3 by isotopic in situ hybridization. The cDNA they used also cross-hybridized to an apparent E2k pseudogene on 1p31.
In 4 unrelated patients (patients 3-6) with pheochromocytoma/paraganglioma syndrome-7 (PPGL7; 618475), Remacha et al. (2019) identified a germline heterozygous missense mutation in the DLST gene (G374E; 126063.0001). Analysis of tumor tissue available from 3 of the patients showed loss of heterozygosity (LOH) for DLST due to uniparental disomy (UPD) of the paternal chromosome. None of the patients had a family history of the disorder, although 3 probands had asymptomatic family members who carried the mutation, consistent with incomplete penetrance; the pedigree in 1 patient suggested de novo occurrence. Knockdown of the DLST gene in human H838 cells resulted in a significant block in carbon flow in the TCA cycle, and this defect could be rescued by wildtype DLST, but not by the G374E mutant. In vitro functional expression studies showed that the G374E mutant had compromised catalytic activity compared to wildtype, resulting in a high alpha-KG/fumarate ratio and accumulation of the oncometabolite 2-hydroxyglutaric acid (2HG), particularly the L-2HG enantiomer. Analysis of patient tumors showed strong immunostaining for DLST as well as a hypermethylated phenotype, categorized in the non-CIMP (CpG island methylator phenotype) cluster, and a pseudohypoxic state with increased expression of HIF3A (609976). The findings indicated that DLST can act as a tumor suppression gene and highlighted abnormalities in the TCA cycle as playing a role in the pathogenesis of paragangliomas. The mutation, which was found by targeted next-generation sequencing of candidate TCA genes among 104 unrelated patients with PGL, was confirmed by Sanger sequencing. Heterozygous missense variants in DLST (R231Q, D304N, and Y422C) were found in 3 additional probands, but in vitro functional studies of these 3 other missense variants indicated that they behaved similar to wildtype DLST in the assay used. Another patient carried a heterozygous splice site mutation, but this was not further studied. None of the patients besides those with the G374E variant showed LOH in tumor tissue. However, Remacha et al. (2019) could not exclude that these variants had other unknown effects.
In 4 unrelated patients (patients 3-6) with paragangliomas (PPGL7; 618475), Remacha et al. (2019) identified a germline heterozygous c.1121G-A transition (c.1121G-A, NM_001933) in exon 14 of the DLST gene, resulting in a gly374-to-glu (G374E) substitution at a highly conserved residue in the catalytic domain. The mutation, which was found by targeted next-generation sequencing of candidate genes in the TCA cycle and confirmed by Sanger sequencing, was present in 2 of 123,121 alleles in the gnomAD database. Analysis of tumor tissue from 3 of the patients showed loss of heterozygosity (LOH) for DLST due to uniparental disomy (UPD) in the paternal chromosome. In vitro functional analysis indicated that the mutation impaired catalytic activity of the protein and resulted in abnormal accumulation of the oncometabolite 2HG.
Ali, G., Wasco, W., Cai, X., Szabo, P., Sheu, K.-F. R., Cooper, A. J. L., Gaston, S. M., Gusella, J. F., Tanzi, R. E., Blass, J. P. Isolation, characterization, and mapping of gene encoding dihydrolipoyl succinyltransferase (E2k) of human alpha-ketoglutarate dehydrogenase complex. Somat. Cell Molec. Genet. 20: 99-105, 1994. [PubMed: 8009371] [Full Text: https://doi.org/10.1007/BF02290679]
Nakano, K., Matuda, S., Sakamoto, T., Takase, C., Nakagawa, S., Ohta, S., Ariyama, T., Inazawa, J., Abe, T., Miyata, T. Human dihydrolipoamide succinyltransferase: cDNA cloning and localization on chromosome 14q24.2-q24.3. Biochim. Biophys. Acta 1216: 360-368, 1993. [PubMed: 8268217] [Full Text: https://doi.org/10.1016/0167-4781(93)90002-u]
Nakano, K., Takase, C., Sakamoto, T., Ohta, S., Nakagawa, S., Ariyama, T., Inazawa, J., Abe, T., Matuda, S. An unspliced cDNA for human dihydrolipoamide succinyltransferase: characterization and mapping of the gene to chromosome 14q24.2-q24.3. Biochem. Biophys. Res. Commun. 196: 527-533, 1993. [PubMed: 8240324] [Full Text: https://doi.org/10.1006/bbrc.1993.2282]
Patel, M. S., Harris, R. A. Mammalian alpha-keto acid dehydrogenase complexes: gene regulation and genetic defects. FASEB J. 9: 1164-1172, 1995. [PubMed: 7672509] [Full Text: https://doi.org/10.1096/fasebj.9.12.7672509]
Remacha, L., Pirman, D., Mahoney, C. E., Coloma, J., Calsina, B., Curras-Freixes, M., Leton, R., Torres-Perez, R., Richter, S., Pita, G., Herraez, B., Cianchetta, G., and 16 others. Recurrent germline DLST mutations in individuals with multiple pheochromocytomas and paragangliomas. Am. J. Hum. Genet. 104: 651-664, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 1008-1010, 2019. [PubMed: 30929736] [Full Text: https://doi.org/10.1016/j.ajhg.2019.02.017]