HGNC Approved Gene Symbol: GCDH
SNOMEDCT: 360416003, 76175005; ICD10CM: E72.3;
Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38): 19:12,891,129-12,899,999 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.13 | Glutaricaciduria, type I | 231670 | Autosomal recessive | 3 |
Glutaryl-CoA dehydrogenase (GCDH; EC 1.3.8.6) is an acyl dehydrogenase involved in the metabolism of lysine, hydroxylysine, and tryptophan. Specifically, it is responsible for the dehydrogenation and decarboxylation of glutaryl-CoA to crotonyl-CoA in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. The active enzyme exists as a homotetramer in the mitochondrial matrix.
Lenich and Goodman (1986) purified the glutaryl-CoA dehydrogenase protein from porcine and human liver mitochondria. Goodman et al. (1992) and Goodman et al. (1995) cloned and sequenced a human GCDH cDNA. Goodman et al. (1995) found that the cDNA encodes a 438-amino acid precursor protein and a 394-amino acid mature protein with a molecular mass of 43.3 kD. The protein shares 92% sequence identity with its porcine homolog. Alternative splicing between exons 10 and 11 produces 2 GCDH mRNA transcripts, only 1 of which is enzymatically active. The precursor protein undergoes 1-step cleavage by mitochondrial processing peptidase to form the mature GCDH subunit.
Koeller et al. (1995) showed that the mouse Gcdh cDNA encodes a predicted protein of 438 amino acids which is highly conserved with respect to the pig and human sequences.
Biery et al. (1996) determined that GCDH gene contains 11 exons and spans approximately 7 kb. Schwartz et al. (1998) reported the sequence of introns 1-3 and 6-9 of the GCDH gene, as well as parts of introns 4, 5, and 10.
Koeller et al. (1995) determined that the mouse gene contains 11 exons and spans about 7 kb of genomic DNA.
By in situ hybridization and somatic cell hybrid analysis, Greenberg et al. (1994) mapped the GCDH gene to chromosome 19p13.2.
Using interspecific backcross mapping, Koeller et al. (1995) mapped the mouse gene to chromosome 8 within a region that has homology of synteny to human chromosome 19.
In a Navajo child with glutaric acidemia type I (GA1; 231670), Biery and Goodman (1992) and Goodman et al. (1995) identified homozygosity for a mutation in the GCDH gene (608801.0001).
Among 64 unrelated patients with glutaric acidemia type I, Biery et al. (1996) identified 12 mutations and several polymorphisms in 7 exons of the GCDH gene (see, e.g., 608801.0007-608801.0009). Several mutations were found in more than one patient, but no one prevalent mutation was detected in the general population. However, a single mutation was found as the cause of glutaric acidemia in the Old Order Amish of Lancaster County, Pennsylvania (A421V; 608801.0002). Biery et al. (1996) expressed several mutations in Escherichia coli; all produced diminished enzyme activity.
Among 8 families with glutaric acidemia I diagnosed in Israel, 6 of Muslim origin and 2 of non-Ashkenazi Jewish background, Anikster et al. (1996) identified 7 mutations in the GCDH gene (see, e.g., 608801.0003). The molecular basis for the clinical variability in GA I families was not revealed by these findings. Anikster et al. (1996) stated that the occurrence of multiple novel alleles in a small geographic area was explained by their recent origin in isolated communities with a high consanguinity rate. In 5 of the families included in this study, the diagnosis of GA I in the index case was followed by identification of another affected sib, who was either asymptomatic, suffered from a milder form of the disease, or was misdiagnosed for a nonmetabolic condition.
Schwartz et al. (1998) reported 21 different mutations in the GCDH gene found in a total of 20 patients with glutaric acidemia type I. These mutations accounted for 38 of 40 mutant alleles in this population.
Goodman et al. (1998) reviewed 63 mutations in the GCDH gene that had been identified by several laboratories as the cause of glutaric acidemia I, 30 of them for the first time. They also reported data on expression in E. coli and the relationship to the clinical and biochemical phenotype. No common GCDH mutation was found, and little if any relationship between genotype and clinical phenotype could be recognized. The mutations were widely distributed through the gene, with the largest number in exon 10.
Zschocke et al. (2000) reported a denaturing gradient gel electrophoresis (DGGE) method for detection of mutations in the GCDH gene. Using this method, they found mutations in both alleles in 48 individuals with confirmed GCDH deficiency. No mutations were found in individuals with clinical suspicion of GCDH deficiency but normal enzyme levels. They identified a total of 38 different mutations; 27 were found in single patients, and 21 mutations were previously unreported. Fourteen mutations involved CpG sites. R402W (608801.0004) was the most common mutation in Europeans, accounting for 40% of alleles in patients of German origin. Zschocke et al. (2000) concluded that the high sensitivity of this method allowed for rapid and cost-efficient diagnosis of glutaricaciduria type I in instances where enzyme analyses are not available or feasible.
Busquets et al. (2000) identified 13 novel and 10 known GCDH mutations in a population of 43 Spanish patients with GA I representing 2 genetically and biochemically distinct groups. Mutations A293T (608801.0007) and R402W (608801.0004) were common (30% and 28%, respectively) in 23 patients with typical biochemical findings, whereas mutations V400M (608801.0008) and R227P (608801.0009) (combined frequency of 53%) were only found in the 17 patients with normal glutarate and mild elevation of 3-hydroxyglutarate by urine organic acid analysis. The severity of the clinical phenotype appeared to correlate with encephalopathic crises, but not with residual enzyme activity or genotype.
By GCDH activity assay in transfected baby hamster kidney cells, Keyser et al. (2008) found that expression of GCDH mutants R138G, R402W (608801.0004), and E414K resulted in a complete lack of enzymatic activity. The M264V mutant had 10% residual activity, and Western blot and pulse-chase analysis indicated that the M263V mutant protein was subject to rapid intramitochondrial degradation. The M263V and R402W mutants showed defective homotetrameric assembly. Molecular modeling of mutant GCDH showed that arg138 and glu414 are both located at the bottom of the active site and required for proper arrangement of the ligand, and that the met263 residue on the surface of the protein might be part of the contact interface to interacting proteins.
By direct sequencing of the GCDH gene in 53 Turkish patients with GA1 from 39 unrelated families, Gurbuz et al. (2020) identified mutations in 46 patients, 40 of whom had homozygous mutations. About 85% of the patients were from consanguineous families. Twenty different mutations, 7 of which were novel, were identified, including 17 missense, 2 deletions, and 1 nonsense. The most common mutations were R402W (608801.0004), P248L, and L340F, with a frequency of 21.2%, 18.2%, and 12.1%, respectively.
Using CRISPR editing, Leandro et al. (2020) developed single and double knockouts for GCDH and DHTKD1 (614984) in HEK293 cells. The GCDH/DHTKD1 double knockout cells had a 2-fold decrease in glutarylcarnitine compared to GCDH knockout cells, but this level was still significantly greater than wildtype cells. Leandro et al. (2020) then showed that the remaining glutarylcarnitine in the GCDH/DHTKD1 double knockout cells was produced via oxoglutarate dehydrogenase (OGDH; 613022), and triple knockout cells for OGDH/GCDH/DHTKD1 had glutarylcarnitine levels that were comparable to wildtype cells. DHTKD1 was shown to physically and functionally interact with OGDH, dihydrolipoyl succinyltransferase, and dihydrolipoamide dehydrogenase to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex. Leandro et al. (2020) concluded that this relationship between DHTKD1 and OGDH limits the therapeutic potential of DHTKD1 for treatment in GA1.
Koeller et al. (2002) generated a mouse model of GA I by targeted deletion of the GCDH gene in embryonic stem cells. The Gcdh -/- mice had a biochemical phenotype very similar to that in patients with GA I, including comparable elevations of glutaric acid and 3-OH glutaric acid. The affected mice had a mild motor deficit but did not develop the progressive dystonia seen in patients. Pathologically, the Gcdh -/- mice had a diffuse spongiform myelinopathy similar to that seen in patients with GA I, but there was no evidence of neuron loss or astrogliosis in the striatum. Subjecting the Gcdh -/- mice to a metabolic stress failed to have any neurologic effect. Koeller et al. (2002) hypothesized that the lack of similarity in regard to the neurologic phenotype and striatal pathology of GA I patients, as compared with the Gcdh -/- mice, may be due to intrinsic differences between the striata of mice and men.
Zinnanti et al. (2006) developed a diet-induced mouse model of GA I by giving increased dietary protein and lysine to Gcdh-null mice. High protein diets were lethal to 4- and 8-week-old Gcdh-null mice within 2 to 3 and 7 to 8 days, respectively. High lysine alone resulted in vasogenic edema and blood-brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, hemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh -/- mice after 3 to 12 days. In contrast, most 8-week-old Gcdh -/- mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Zinnanti et al. (2006) concluded that the Gcdh -/- mouse exposed to high protein or lysine is a model of human GA I, including developmentally dependent striatal vulnerability.
Zinnanti et al. (2007) demonstrated that Gcdh expression was restricted to neurons in normal mouse brain. Gcdh-deficient mice showed an age-dependent susceptibility to encephalopathy, with weanling mice showing more neuronal damage than adult mice after exposure to dietary protein. Pathologic changes included vacuolated neurons and dendritic processes with enlarged mitochondria and neurofilament disorganization. Weanling Gcdh-deficient mice showed higher brain lysine and glutaric acid accumulation compared to heterozygous controls, whereas adult Gcdh-deficient mice showed no increase in these levels, consistent with decreased brain lysine uptake with maturity. Increased brain lysine and glutaric acid in weanling Gcdh-deficient mice correlated with brain injury, encephalopathy, and symptoms. The biochemical changes induced mitochondrial swelling and functional disruption. Treatment by limiting brain lysine uptake and decreasing brain lysine catabolism resulted in improved survival and decreased brain injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (NMR) spectroscopy as a diagnostic marker. The findings indicted that the age-dependent brain injury of GA I involves mitochondrial disruption precipitated by glutaric acid production from lysine in the neuronal compartment.
Gonzalez Melo et al. (2021) developed a rat knock-in model of GA I that was homozygous for an R411W mutation in exon 12 of the Gcdh gene, which corresponds to the human R402W (608801.0004) mutation in the GCDH gene. On a regular diet, the mutant mice did not show signs of encephalopathic crises. However, when the mutant rats were fed a high (5%) lysine diet, they exhibited lethargy, stiffness, imbalance, and spasticity. The mutant rats fed a high lysine diet also had significantly reduced food intake, resulting in decreased weight and body mass index. They demonstrated increased plasma ammonium, decreased plasma urea, and increased urine arginine, suggesting dysfunction of the urea cycle. The mutant rats on a high lysine diet were also found to have increased pipecolic acid in the plasma, urine, and striatum, suggesting upregulation of alternative mechanisms of lysine degradation. Examination of brain tissue from 6-week-old mutant rats fed a high lysine diet showed microglial activation, astrogliosis, and increased vacuolation. Free carnitine was low in the striatal tissue and urine of these mice, but not in plasma or CSF, indicating intracellular depletion of carnitine.
Gonzalez Melo et al. (2021) evaluated the kidney phenotype of the knock-in R411W rat model. In 6-week-old knock-in mice fed a high lysine diet, there was a decline in glomerular filtration rate and electrolyte excursions consistent with a renal tubulopathy including hypocalcemia, hypokalemia, hypophosphatemia, hypobicarbonatemia, and hyperchloremia. Gonzalez Melo et al. (2021) also observed a decrease in glomerular filtration rate in 12-month-old knock-in mice fed a normal diet. Microscopic examination of the kidneys of 6-week-old knock-in mice fed a high lysine diet showed increased numbers of mitochondria, lipophilic vacuoles, and thinned apical brush border membranes in proximal tubules. In addition, enzymatic studies in kidneys of 6-week-old knock-in mice fed a high lysine diet demonstrated reduced activities of complexes I, III, and V of the respiratory chain. Proteomic studies of kidneys from the knock-in mice demonstrated dysregulation of 127 proteins associated with mitochondrial function. Gonzalez Melo et al. (2021) concluded that GA I leads to acute and chronic kidney damage.
In a patient with glutaric acidemia I (GA1; 231670) whose parents were probably consanguineous, Biery and Goodman (1992) demonstrated homozygosity for a T-to-C transition in the GCDH gene, resulting in a tyr195-to-his substitution. Goodman et al. (1995) reported further studies of this patient and found that the mutation was actually a tyr295-to-his substitution rather than TYR195HIS. and corrected the identity of the mutation, which is tyr295-to-his (Y295H) rather than TYR195HIS. The patient was a Navajo child in whom symptoms began with chorea at the age of 4 months and whose fibroblasts were almost totally deficient in GCDH activity. The child appeared to be homozygous for the T-to-C transition at nucleotide 919 of their sequence. The mutation was not identified in control subjects or in more than 50 other GA I patients. Expression studies in E. coli showed that the mutant Y295H GCDH protein was stable but inactive. Homology modeling against the crystal structure of median-chain acyl-CoA dehydrogenase (607008) suggested that Y295 may lie near the adenine ring of the CoA moiety of glutaryl-CoA and interfere with substrate binding.
In the Old Order Amish of Lancaster County, Pennsylvania, Biery et al. (1996) found that the type I glutaric acidemia (GA1; 231670) was caused in all cases by homozygosity for a 1298C-T transition in the GCDH gene, resulting in an ala421-to-val (A421V) amino acid substitution. In 4 non-Amish patients with glutaric acidemia type I, Biery et al. (1996) found compound heterozygosity for mutations in the GCDH gene, with 1 allele being the A421V 'Amish' gene; all these patients had some central European ancestry. Expression studies of the A421V mutation in E. coli showed reduced enzyme activity, which the authors suggested was due to impaired association of enzyme subunits.
Strauss et al. (2007) referred to the Amish mutation as 1296C-T.
In the course of studying Arab and non-Ashkenazi Jewish patients in Israel with glutaric acidemia I (GA1; 231670), Anikster et al. (1996) identified a family in which at least 3 sibs were homozygous for an ACA-to-ATA transition in codon 416 of the GCDH gene, resulting in a thr416-to-ile (T416I) amino acid substitution. Remarkably, 1 of 3 homozygous sibs was asymptomatic and the asymptomatic father was also homozygous for the same mutation. The mother was a heterozygote for the T416I mutation.
In a large study of 48 European patients with glutaric acidemia I (GA1; 231670), Zschocke et al. (2000) found that the most common GCDH mutation was a 1204C-T change, resulting in an arg402-to-trp (R402W) substitution; it was present in 14 of 36 alleles (40%) in patients of German origin.
Kolker et al. (2001) described a patient with glutaricaciduria type I (GA1; 231670) who was homozygous for a glu365-to-lys (E365K) substitution in the GCDH gene, a mutation previously described by Zschocke et al. (2000). This mutation is known to result in approximately 1% residual enzyme activity, causing high levels of 3-hydroxyglutaric acid and glutaric acid in plasma and urine.
In 10 patients with glutaric acidemia I (GA1; 231670) from an inbred Aboriginal population in northern Manitoba and northwestern Ontario, Greenberg et al. (1995) identified homozygosity for a G-to-T transversion at position +5 of IVS1 of the GCDH gene.
In patients with glutaric acidemia I (GA1; 231670), Biery et al. (1996) identified homozygosity for a 913G-A transition in the GCDH gene, resulting in an ala293-to-thr (A293T) substitution.
In patients with glutaric acidemia I (GA1; 231670), Biery et al. (1996) identified homozygosity for a 1234G-A transition in the GCDH gene, resulting in a val400-to-met (V400M) substitution.
Marti-Masso et al. (2012) reported 2 adult Spanish sisters with onset in infancy of a severe progressive form of dystonia affecting the upper and lower limbs, face, neck, and trunk, and resulting in severe speech impairment and the inability to walk by the teenage years. Neither had macrocephaly, organomegaly, cognitive impairment, or acute encephalopathy in childhood. Whole-exome sequence analysis identified a homozygous V400M mutation, consistent with glutaric acidemia. Laboratory studies showed decreased long-chain acylcarnitines and high excretion of 3-hydroxyglutaric acid, but urinary glutaric acid excretion was normal. Brain imaging showed increased signals in the lenticular nuclei. The findings implicated mitochondrial fatty acid metabolism as an important pathway in the development of dystonia, and Marti-Masso et al. (2012) concluded that GCDH mutation analysis should be considered in the differential diagnosis of progressive forms of early-onset generalized dystonia.
In patients with glutaric acidemia I (GA1; 231670), Biery et al. (1996) identified homozygosity for a 716G-C transversion in the GCDH gene, resulting in an arg227-to-pro (R227P) substitution.
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