Alternative titles; symbols
HGNC Approved Gene Symbol: DLD
SNOMEDCT: 124184009, 767497003; ICD10CM: D74.0;
Cytogenetic location: 7q31.1 Genomic coordinates (GRCh38) : 7:107,891,107-107,921,198 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q31.1 | Dihydrolipoamide dehydrogenase deficiency | 246900 | Autosomal recessive | 3 |
The DLD gene encodes dihydrolipoamide dehydrogenase (EC 1.8.1.4), a flavoprotein component known as E3 that is common to the 3 alpha-ketoacid dehydrogenase multienzyme complexes, namely, pyruvate dehydrogenase complex (PDC), the alpha-ketoglutarate dehydrogenase complex (KGDC), and the branched-chain alpha-keto acid dehydrogenase complex (BCKDC). The enzyme is a functional homodimer of the DLD protein and catalyzes the oxidative regeneration of a lipoic acid cofactor covalently bound to E2 (DBT; 248610) yielding NADH. The DLD enzyme is also a component, referred to as the L protein, of the mitochondrial glycine cleavage system (GCS; EC 2.1.2.10). In addition, DLD has cryptic activities as a diaphorase and a serine protease (summary by Hong et al., 1996 and Vaubel et al., 2011).
Using a cDNA corresponding to lipoamide dehydrogenase isolated from a porcine adrenal medulla library, Otulakowski and Robinson (1987) isolated the corresponding human cDNA. The deduced amino acid sequence shows 96% identity to the porcine protein and extensive homology to human erythrocyte glutathione reductase and mercuric reductase.
Pons et al. (1988) isolated cDNA clones comprising the entire coding region for dihydrolipoamide dehydrogenase from a human liver cDNA library. The sequence encodes a deduced 509-amino acid precursor protein. The mature E3 enzyme is a homodimer, and each subunit has a molecular mass of about 50 kD. Blot hybridization analysis detected 2 mRNA transcripts, 2.2 and 2.4-kb, in human tissues and fibroblasts.
Using somatic cell hybrids, Otulakowski et al. (1988) assigned the gene for lipoamide dehydrogenase to chromosome 7. Olson et al. (1990) confirmed the assignment of the E3 gene to chromosome 7. Scherer et al. (1991) refined the localization to 7q31-q32.
By interspecies backcross analysis, Johnson et al. (1997) mapped the mouse Dld gene to the proximal region of chromosome 12, a region that shows homology of synteny with human 7q31-q32.
Feigenbaum and Robinson (1993) determined that the DLD gene contains 14 exons.
The mitochondrial glycine cleavage system (GCS; EC 2.1.2.10) is a multienzyme system comprising 4 components referred to as P (238300), H (238330), T (238310), and L proteins. L protein represents dihydrolipoamide dehydrogenase, a housekeeping enzyme that serves as a component of other complex enzyme systems such as the pyruvate dehydrogenase complex (see 300502) and the branched chain ketoacid dehydrogenase complex (see 608348) (Sakata et al., 2001). No defect in the L protein has been identified as the cause of glycine encephalopathy (605899); see review of Hamosh and Johnston (2001).
Petrat et al. (2003) found that DLD catalyzes the one-electron reduction of Fe3+ complexes of citrate, ATP, and ADP from NAD(P)H, indicating a role for the enzyme in intracellular metabolism of the labile iron pool. The findings had implications for the fate of iron in transit, which has a substantial cytotoxic potential via iron-dependent generation of reactive oxygen species.
Babady et al. (2007) found that destabilization of the DLD homodimer to a monomer enabled the enzyme to function as a serine protease. A catalytic dyad (S456-E431) buried at the homodimer interface was identified. Mutations at the 456 or 431 residues abolished the proteolytic activity. Proteolytically active DLD removed a functional critical domain from the N terminus of frataxin (FXN; 606829), a mitochondrial protein involved in iron metabolism and antioxidant protection. Mutation in FXN causes the neurodegenerative and cardiac disease Friedreich ataxia (FRDA; 229300).
During enzymatic activity, DLD oxidizes dihydrolipoic moieties and generates NADH from NAD+ in a forward reaction, whereas it reduces model substrates like lipoic acid or lipoamide and oxidizes NADH to NAD+ in a reverse reaction. If the NAD+ or lipoic acid electron-acceptor substrate is scarce, O2 can be reduced to a superoxide anion and then dismutated to H2O2, generating reactive oxygen species (ROS). DLD thus acts as a diaphorase, reducing various organic molecules via the transfer of a single electron. Monomerization of DLD is thought to transform its activity to a diaphorase (summary by Ambrus et al., 2011).
In a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900) reported by Sakaguchi et al. (1986), Liu et al. (1993) demonstrated compound heterozygosity for missense mutations in the DLD gene (238331.0001 and 238331.0002).
Among 13 affected patients from 7 Ashkenazi Jewish families with LAD deficiency, Shaag et al. (1999) identified a mutation (G229C; 238331.0006) in the DLD gene in 12 of 14 mutated alleles. The other 2 alleles had a previously identified insertion mutation (238331.0003). Homozygosity for the G229C mutation was associated with a relatively milder phenotype.
In a patient with E3 deficiency who developed clinical characteristics of Leigh syndrome (256000), Grafakou et al. (2003) identified heterozygosity for 2 novel mutations in the DLD gene (238331.0007 and 238331.0008).
Babady et al. (2007) found that some DLD mutations at the homodimer interface domain enhanced serine proteolytic activity, while also causing partial or complete loss of DLD activity. The findings indicated a mechanism by which certain DLD mutations could induce the loss of a primary metabolic activity and the gain of a proteolytic activity.
By in vitro functional analysis of DLD mutations purified in E. coli, Ambrus et al. (2011) found that the D479V (238331.0011), E375K (238331.0009), P488L (238331.0002), and G194C (238331.0006) mutations significantly increased the rate of generation of reactive oxygen species compared to controls and to other mutations (e.g., K72E, 238331.0001). These 4 mutants also showed increased sensitivity of ROS generation to an acidic shift in pH. There was no correlation between conformational change in the mutant proteins or monomerization and the ability to generate ROS. The findings suggested that the generation of ROS may also contribute to the disease in some cases, and that the use of antioxidants may be beneficial.
By in vitro functional analysis in E. coli, Vaubel et al. (2011) found that all pathogenic DLD mutations caused variable degrees of decreased DLD activity. However, those at the dimer interface that were associated with severe multisystem disorders of infancy, including E375K, D479V, R48G (238331.0012), and R460G, also enhanced proteolytic and/or diaphorase activity of DLD. Human DLD proteins carrying each individual mutation complemented the respiratory-deficient phenotype of yeast cells lacking endogenous DLD even when residual DLD activity was as low as 21% of controls. However, under elevated oxidative stress or with time, expression of DLD proteins with dimer interface mutations greatly accelerated the loss of respiratory function, resulting from enhanced oxidative damage to the lipoic acid cofactor of PDC and KGDC and other mitochondrial targets. This effect was not observed with the G194C mutation, which affects the NAD(+)-binding domain and is generally associated with a milder phenotype, or a mutation that disrupts the proteolytic active site of DLD. Lipoic acid cofactor was also damaged in human D479V-homozygous fibroblasts after exposure to oxidative stress. DLD mutations affecting the dimer interface also appeared to affect FXN turnover. Vaubel et al. (2011) concluded that the cryptic activities of DLD can promote oxidative damage and may thus contribute to the variable clinical severity of DLD mutations in addition to mutational effects on enzyme activity.
In a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900) reported by Sakaguchi et al. (1986), Liu et al. (1993) demonstrated compound heterozygosity for missense mutations in the DLD gene: an A-G change, resulting in a lys72-to-glu (K72E) substitution (K37E in the processed protein, Odievre et al., 2005), and a C-T change, resulting in a pro488-to-leu (P488L; 238331.0002) substitution (P453L in the processed protein, Odievre et al., 2005). These mutations altered the active site and possibly the binding of FAD.
By in vitro functional expression studies, Ambrus et al. (2011) found that the P453L mutation resulted in a significant decrease in LADH activity as well as a significant increase in the generation of reactive oxygen species.
For discussion of the pro488-to-leu (P488L) mutation in the DLD gene that was found in a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900) by Liu et al. (1993), see 238331.0001.
In a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900), who was originally reported by Craigen (1996), Hong et al. (1996) identified compound heterozygosity for 2 mutations in the DLD gene: a 1-bp insertion (105insA) in the last codon of the leader sequence predicted to result in a frameshift and premature termination (Y35X), and an arg495-to-gly (R495G; 238331.0004) substitution (R460G in the processed protein, Odievre et al., 2005). The patient had developmental delay, hypotonia, metabolic acidosis (elevated serum lactate and pyruvate), a history of transient neonatal hypoglycemia, and features of Leigh syndrome; she died at age 28 months. Plasma amino acid analysis in the patient initially showed increased leucine, isoleucine, and valine. Urine organic acid analysis showed mild to moderate increases of lactic, 2-hydroxybutyric, 3-hydroxybutyric, alpha-ketoglutaric, and 3-hydroxyisovaleric acids. She died at age 28 months. Activities of the PDC and E3 in patient lymphocytes were 26% and 2% of control values, respectively, and in patient fibroblasts were 11% and 14%, respectively. KGDC activity in fibroblasts was 20%. Corresponding values in the clinically unaffected parents were about 50% of normal, except for KGDC, which was normal. These findings suggested that a partial reduction in E3 is not rate-limiting for KGDC activity in fibroblasts. Glycine was also not increased in the patient.
In 2 unrelated patients of Ashkenazi-Jewish origin with DLDD, Elpeleg et al. (1997) identified the 105insA mutation in the DLD gene. The 2 patients were heterozygotes for the mutation; no other mutation was identified in the coding region. Heterozygosity for the 105insA mutation was also identified in the cDNA of the father and 1 brother of patient 1, and in the mother and 1 sister of patient 2. Because the enzymatic activity of lipoamide dehydrogenase in muscle tissue of both patients was reduced to 8 to 20% of the control mean, Elpeleg et al. (1997) presumed that both patients were compound heterozygotes for this and another unidentified mutation.
For discussion of the arg495-to-gly (R495G) mutation in the DLD gene that was found in compound heterozygous state in a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900) by Hong et al. (1996), see 238331.0003.
In a series of 7 Ashkenazi Jewish families with dihydrolipoyl dehydrogenase deficiency (DLDD; 246900), Shaag et al. (1999) identified a mutation in the DLD gene resulting in a gly229-to-cys (G229C) substitution at a highly conserved residue in the NAD(+)-binding domain. The G229C mutation accounted for 12 of 14 mutant alleles. G229C corresponds to G194C in the mature protein (Odievre et al., 2005). In a sample of 845 anonymous individuals of Ashkenazi Jewish origin, 9 heterozygotes for the G194C mutation were identified, yielding a carrier rate of 1:94. The other 2 alleles in the series had a previously identified insertion mutation (238331.0003). The disease course and age at onset were highly variable. Some patients had few neurologic sequelae and long survival. Two patients presented immediately after birth, 9 around age 2 years, and 2 as adults. All had recurrent episodes of vomiting, abdominal pain, and hepatomegaly, usually associated with neurologic signs during the episodes. Episodes were associated with lactic acidosis, abnormal liver enzymes, and prolonged prothrombin time. Biochemical anomalies, such as increased branched-chain amino acids and increased alpha-ketoacids were not commonly found. The 2 patients who presented neonatally had residual neurologic damage with attention deficit-hyperactivity disorder, mild ataxia, motor incoordination, muscle hypotonia, and weakness. Nine patients who presented in early childhood or as adults suffered from exertional fatigue between episodes of decompensation but were otherwise asymptomatic and showed normal psychomotor development. Two patients died because of intractable metabolic acidosis and multiorgan failure. In all patients, E3 activity was reduced to 8 to 21% of the control value in muscle or lymphocytes. In 4 patients tested, the E3 protein in muscle was reduced to 20 to 60% of control.
Hong et al. (2003) reported 2 sibs, born of consanguineous Palestinian Arab Muslim parents, with E3 deficiency due to homozygosity for the G194C mutation. A girl died in infancy during an episode of repeated vomiting associated with encephalopathy. Two previous sibs had died under similar circumstances. A brother had recurrent episodes of vomiting associated with encephalopathy from age 8 months. Examination at age 10 years showed generalized muscle weakness and wasting, ataxic gait, hepatomegaly, and lactic acidemia. He was treated with riboflavin, coenzyme Q, biotin, and carnitine. Six years later, he was functioning well at a normal school, but had slight ataxia and intention tremor. Two additional patients, both of Ashkenazi Jewish descent, had a severe form of E3 deficiency and the G194C mutation. One had repeated episodes of hypoglycemia and was in a persistent vegetative state at age 4 years; he died soon after. A girl had recurrent episodes of repeated vomiting and acidosis since infancy; she died of hepatic failure at age 5 years. All patients had decreased levels of the E3 protein (range, 35-68% of controls) and decreased E3 activity (8-33% of controls). Hong et al. (2003) emphasized the favorable outcome in the 1 child treated with riboflavin and additional supplements.
By in vitro functional expression studies, Ambrus et al. (2011) found that the G194C mutant protein caused no significant changes in LADH activity but did result in significantly increased generation of reactive oxygen species.
In a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900), Grafakou et al. (2003) identified heterozygosity for 2 mutations in the DLD gene: an ile393-to-thr (I393T) substitution in exon 11, postulated to interfere with protein dimerization, and an IVS9+1G-A change at a consensus splice site (238331.0008). I393T corresponds to I358T in the mature protein (Odievre et al., 2005). The I358T mutation cosegregated with a polymorphism, 1422A-C, in exon 13; both appeared to be homozygous in cDNA studies, suggesting that the mRNA product of the splice site mutation was unstable. One year after presentation, the patient developed a stroke-like episode, and brain MRI showed symmetric hyperintensity consistent with Leigh syndrome (256000).
For discussion of the splice site mutation in the DLD gene (IVS9+1G-A) that was found in compound heterozygous state in a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900) by Grafakou et al. (2003), see 238331.0007.
In a 10-week-old boy with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900), Cerna et al. (2001) identified compound heterozygosity for 2 mutations in the DLD gene: a 1123G-A transition resulting in a glu375-to-lys (E375K) substitution and a 1081A-G transition resulting in a met361-to-val (M361V; 238331.0010) substitution. E375K and M361V correspond to E340K and M326V in the mature protein, respectively (Odievre et al., 2005). DLD activity in the patient's lymphocytes, muscle mitochondria, and fibroblasts was less than 5% of control values, and Western blot analysis showed a decrease in DLD protein levels to 40% of controls.
Cameron et al. (2006) noted that the E375K mutation occurs at a conserved residue in the central domain of DLD.
For discussion of the met361-to-val (M361V) mutation in the DLD gene that was found in compound heterozygous state in a patient with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900) by Cerna et al. (2001), see 238331.0009.
In a 9-month-old girl of Muslim origin with a severe neurodegenerative form of dihydrolipoamide dehydrogenase deficiency (DLDD; 246900), Shany et al. (1999) identified a homozygous 1436A-T transversion in the DLD gene, resulting in an asp479-to-val (D479V) substitution, which is a D444V change in the processed protein (Odievre et al., 2005). The substitution occurs in the interface domain of the DLD dimer, which was postulated to perturb the stability of the homodimer. The patient reported by Shany et al. (1999) presented on the third day of life with apathy, poor feeding, and lethargy. Laboratory studies showed hypoglycemia and severe lactic acidosis, but normal levels of branched-chain keto acids and alpha-ketoglutarate. Muscle biopsy showed no activity of the pyruvate dehydrogenase complex, severely decreased activity of the alpha-ketoglutarate dehydrogenase complex (2%), and decreased DLD activity at 15% of controls. Each of her unaffected parents had about 50% reduced DLD protein activity. She had recurrent episodes of metabolic acidosis, often triggered by infection. Clinical features included microcephaly, lack of psychomotor development, blindness, deafness, hypotonia, brisk reflexes, and mild hypertrophic cardiomyopathy. Shany et al. (1999) noted that the phenotypic severity in this patient was not correlated with residual DLD protein activity, since the G229C mutation (238331.0006) was associated with even less activity (7%), but a milder phenotype.
Babady et al. (2007) found that the D444V mutant protein had increased proteolytic activity compared to wildtype and that this proteolytic activity correlated with the monomer fraction of the mutant DLD protein. The appearance of this proteolytic activity may have contributed to the phenotypic severity.
In 3 Algerian sibs, born of consanguineous parents, with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900), Odievre et al. (2005) identified a homozygous 1444A-G transition in exon 13 of the DLD gene, resulting in an arg482-to-gly (R482G) substitution (R447G in the processed protein) in the dimer interface domain. The patients had originally been reported by Bonnefont et al. (1992) as having alpha-ketoglutarate dehydrogenase deficiency. They had a severe form of the disorder, resulting in death in all by age 30 months.
In 2 second-cousin Ashkenazi Jewish patients with dihydrolipoamide dehydrogenase deficiency (DLDD; 246900), Cameron et al. (2006) identified compound heterozygosity for 2 mutations in the DLD gene. Both patients carried a heterozygous T-to-C transition in exon 3, resulting in an ile47-to-thr (I47T) substitution at a highly conserved region in the FAD functional domain. One patient had G229C (238331.0006) on the other allele, and the other had E375K (238331.0009) on the other allele. All unaffected parents were heterozygous for 1 of the mutations. Both patients had decreased activities of the KGDH (25% and 44%, respectively) and BCKDH (58% and 62%, respectively) complexes, but PDH complex activity was at the low end of normal (69% and 59%, respectively). DLD activity was decreased in both patients. The patient with the G229C mutation had a milder phenotype compared to the patient without that mutation.
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