Alternative titles; symbols
HGNC Approved Gene Symbol: ACADVL
SNOMEDCT: 237997005; ICD10CM: E71.310;
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38) : 17:7,217,125-7,225,266 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | VLCAD deficiency | 201475 | Autosomal recessive | 3 |
The ACADVL gene encodes very long-chain acyl-CoA dehydrogenase (VLCAD) (EC 1.3.99.13). VLCAD is unique among the acyl-CoA dehydrogenases in its size, structure, and intramitochondrial distribution (Aoyama et al., 1995).
Izai et al. (1992) identified and purified a novel acyl-CoA dehydrogenase, Acadvl, from rat liver mitochondria.
Aoyama et al. (1995) cloned and sequenced 2 overlapping cDNA clones corresponding to human mitochondrial VLCAD. The cDNA encodes a 655-amino acid protein with a 40-amino acid leader peptide, yielding a mature 615-residue protein.
Whereas the other acyl-CoA dehydrogenases are homotetramers of a 43- to 45-kD subunit, VLCAD purified from human liver was shown by Aoyama et al. (1995) to be a 154-kD homodimer of a 70-kD subunit. VLCAD was loosely bound to the mitochondrial inner membrane and required detergent for stabilization. In contrast, the other 3 acyl-CoA dehydrogenases others were readily extractable into the soluble fraction without detergent, indicating that they are located in the mitochondrial matrix.
Andresen et al. (1996) isolated cDNA clones for human VLCAD by using rat Vlcad cDNA sequences to identify an EST from human fetal brain in the GenBank database, followed by 5-prime and 3-prime rapid amplification of cDNA ends (RACE) to identify overlapping clones. Sequence analysis of the coding region and the 5-prime noncoding region of the VLCAD cDNA showed no differences with the sequence published by Aoyama et al. (1995). Andresen et al. (1996) found 26 to 33% homology between VLCAD and other human acyl-CoA dehydrogenases. Northern blot analysis detected a 2.4-kb mRNA transcript in a variety of human tissues.
By real-time RT-PCR, Zhou and Blumberg (2003) detected VLCAD expression in all tissues examined, with highest expression in heart and skeletal muscle, followed by placenta and pancreas.
Izai et al. (1992) found that the properties of Acadvl purified from rat liver mitochondria differed from those of the short (ACADS; 606885)-, medium (ACADM; 607008)-, and long (ACADL; 609576)-chain acyl-CoA dehydrogenases. Acadvl was active toward very long-chain fatty acids.
Aoyama et al. (1995) found that human VLCAD had 10 times higher specific activity toward palmitoyl-CoA than did LCAD. The enzyme was found to catalyze the major part of mitochondrial palmitoyl-CoA dehydrogenation in liver, heart, skeletal muscle, and skin fibroblasts.
Strauss et al. (1995) determined that the ACADVL gene contains 20 exons. The ACADVL gene is about 5.4 kb long (Zhou and Blumberg, 2003).
Zhang et al. (2003) noted that the VLCAD and the DLG4 (602887) genes are located in a head-to-head orientation on chromosome 17p. The transcribed regions of the 2 genes overlap by about 220 bp. Using serial promoter partial deletion constructs in a reporter gene assay, they found that the essential promoter activity of DLG4 is carried within a region of about 400 bp and covers the entire VLCAD minimal promoter, which spans about 270 bp. The results from di-(2-ethylhexyl) phthalate (DEHP)-treated HepG2 cells revealed that the minimal VLCAD promoter can upregulate VLCAD expression in response to DEHP treatment. Site-directed mutagenesis experiments showed that a mutated AP2 (107580)-binding site markedly reduced the transcriptional activity of both the VLCAD and DLG4 promoters and abolished the minimal VLCAD promoter's response to DEHP treatment.
Independently, Zhou and Blumberg (2003) determined that the VLCAD and DLG4 genes overlap. The 2 genes share 245 nucleotides at their 5-prime ends, and the transcription start site for DLG4 extends into the coding region of VLCAD exon 1. The upstream regions of the VLCAD and DLG4 genes, including the overlapping region, contain 2 potential TATA-less promoters with potential binding sites for several common transcription factors. RT-PCR detected unique patterns of expression for VLCAD and DLG4, indicating that, although they share common regulatory elements, VLCAD and DLG4 also have distinct tissue-specific elements. The mouse Dlg4 and Vlcad genes are oriented in a head-to-head manner, but they do not overlap and are separated by almost 3.5 kb.
Andresen et al. (1996) mapped the ACADVL gene to human chromosome 17p13.1-p11.2 by analysis of rodent-human hybrids.
By fluorescence in situ hybridization, Orii et al. (1997) mapped the murine Acadvl gene to chromosome 11 in a region of synteny to human 17p13.
In cultured fibroblasts of 2 patients with VLCAD deficiency (201475), Aoyama et al. (1995) identified a 105-bp deletion in the ACADVL gene (609575.0001).
Andresen et al. (1996) identified 9 different mutations in the ACADVL gene in 4 unrelated patients with VLCAD deficiency. Two patients carried 3 different mutations. Different mutations were observed in each of the patients. Western blot analysis on fibroblasts from 3 of the patients revealed severe quantitative reduction in VLCAD protein.
Mathur et al. (1999) identified 21 different mutations in the ACADVL gene in 18 of 37 children with cardiomyopathy, nonketotic hypoglycemia and hepatic dysfunction, skeletal myopathy, or sudden death in infancy with hepatic steatosis. Sixty-seven percent of children had severe dilated or hypertrophic cardiomyopathy at presentation. In 7 patients, only 1 mutation was found despite direct sequencing of all exons. Missense, frameshift, and splice consensus sequence mutations were seen, as well as in-frame deletions. Eighty percent of these mutations were associated with cardiomyopathy. The authors concluded that infantile cardiomyopathy is the most common clinical phenotype for VLCAD deficiency and highlighted the marked allelic heterogeneity in this disorder.
Since VLCAD-deficient patients frequently harbor missense mutations with unpredictable effects on enzyme activity, Gobin-Limballe et al. (2007) investigated the response to bezafibrate as a function of genotype in 33 VLCAD-deficient fibroblast cell lines representing 45 different mutations. Treatment with bezafibrate (400 microM for 48 hours) resulted in a marked increase in FAO capacities, often leading to restoration of normal values, for 21 genotypes that mainly corresponded to patients with the myopathic phenotype. In contrast, bezafibrate induced no changes in FAO for 11 genotypes corresponding to severe neonatal or infantile phenotypes. This pattern of response was not due to differential inductions of VLCAD mRNA, as shown by quantitative real-time PCR, but reflected variable increases in measured VLCAD residual enzyme activity in response to bezafibrate. Genotype cross-analysis allowed the identification of alleles carrying missense mutations, which could account for these different pharmacologic profiles and, on this basis, led to the characterization of 9 mild and 11 severe missense mutations. The responses to bezafibrate reflected the severity of the metabolic blockage in various genotypes, which appeared to be correlated with the phenotype. This study emphasized the potential of bezafibrate, a widely prescribed hypolipidemic drug, for the correction of VLCAD deficiency and exemplified the integration of molecular information in a therapeutic strategy.
Of the 52 patients with VLCAD deficiency reported by Pena et al. (2016), molecular testing was available for 46. Two mutations were identified in 44 of these while only 1 mutation was identified in the remaining 2. Most (38 of 46, 83%) were compound heterozygous, and of the 50 different alleles reported, 26 were novel. Evans et al. (2016) reported 5 novel mutations among 22 patients with VLCAD deficiency identified in Victoria, Australia.
Cox et al. (2001) generated mice with VLCAD deficiency (Vlcad -/-) and compared their pathologic and biochemical phenotypes to mice with Lcad deficiency (Lcad -/-) and wildtype mice. Vlcad -/- mice had milder fatty acid change in liver and heart. Dehydrogenation of various acyl-CoA substrates by liver, heart, and skeletal muscle mitochondria differed among the 3 genotypes. The results for liver were most informative as Vlcad -/- mice had a reduction in activity toward palmitoyl-CoA and oleoyl-CoA (58% and 64% of wildtype, respectively), whereas Lcad -/- mice showed a more profoundly reduced activity toward these substrates (35% and 32% of wildtype, respectively), with a significant reduction of activity toward the branched chain substrate 2,6-dimethylheptanoyl-CoA. C16 and C18 acylcarnitines were elevated in bile, blood, and serum of fasted Vlcad -/- mice, whereas abnormally elevated C12 and C14 acylcarnitines were prominent in Lcad -/- mice. Progeny with the combined Lcad +/+//Vlcad +/- genotype were overrepresented in offspring from sires and dams heterozygous for both Lcad and Vlcad mutations. In contrast, no live mice with a compound Lcad -/-/Vlcad -/- genotype were detected, suggesting that this genotype may be lethal in utero or in the periparturient period.
To define the onset and molecular mechanism of myocardial disease, Exil et al. (2003) generated Vlcad-deficient mice by homologous recombination. They found that Vlcad-deficient hearts had microvesicular lipid accumulation and marked mitochondrial proliferation, and demonstrated facilitated induction of polymorphic ventricular tachycardia, without antecedent stress. The expression of acyl-CoA synthetase-1 (ACS1; 152425), adipophilin, Ap2, cytochrome c, and the peroxisome proliferator-activated receptor-gamma coactivator-1 (PPARGC1; 604517) were increased immediately after birth, preceding overt histologic lipidosis, whereas Acs1 expression was markedly downregulated in the adult heart. Exil et al. (2003) concluded that mice with Vlcad deficiency have altered expression of a variety of genes in the fatty acid metabolic pathway from birth, reflecting metabolic feedback circuits, with progression to ultrastructural and physiologic correlates of the associated human disease in the absence of stress.
In 2 patients with VLCAD deficiency (201475), Aoyama et al. (1995) identified a 105-bp deletion encompassing bases 1078-1182 in the VLCAD cDNA. The deletion was thought to result from exon skipping and was predicted to result in the in-frame deletion of 35 amino acids, beginning with val360 of the precursor VLCAD. Using the vaccinia viral system, Aoyama et al. (1995) performed quantitative cDNA expression of normal human VLCAD in the patients' fibroblasts and demonstrated that raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts. The mutation described in these patients has consequences for enzyme folding and assembly that are similar to those for the well-characterized A985G mutation (lys329-to-glu; 607008.0001) found in approximately 90% of the mutant alleles in patients with MCAD deficiency (201450).
In a patient with VLCAD deficiency (201475) associated with infantile cardiomyopathy and sudden death, Strauss et al. (1995) identified a homozygous G-to-A transition in the consensus dinucleotide of the donor splice site in intron 11 of the ACADVL gene, resulting in the skipping of exon 11.
In a patient with VLCAD deficiency (201475), Souri et al. (1996) identified compound heterozygosity for 2 mutations in the ACADVL gene: a 1837C-T transition, resulting in an arg613-to-trp (R613W) substitution, and a 135-bp deletion of nucleotides 343-477, resulting in the loss of 45 amino acids from the VLCAD protein (609575.0005).
In a patient with VLCAD deficiency (201475) associated with infantile cardiomyopathy and sudden death, Strauss et al. (1995) identified compound heterozygosity for 2 mutations in the ACADVL gene: R613W (609575.0003) and a 1-bp deletion of one of the 2 guanine nucleotides forming the intron-exon 6 boundary. The normal sequence is ccccagGAA and the mutant sequence was cccaGAA. The authors noted that the most likely consequence of this deletion would be an alternation in splicing because of loss of the conserved ag dinucleotide at the splice acceptor site. Alternatively, splicing at this site might occur but this would result in loss of a single nucleotide in exon 6, causing a shift in the mRNA reading frame. In either event, this mutation would most likely result in an unstable mRNA and lack of VLCAD protein expression from the mutant allele.
For discussion of the 135-bp deletion of nucleotides 343-477 in the ACADVL gene, resulting in the loss of 45 amino acids, that was found in compound heterozygous state in a patient with VLCAD deficiency (201475) by Souri et al. (1996), see 609575.0003.
In a patient with VLCAD deficiency (201475), Souri et al. (1996) identified a homozygous 3-bp deletion in the ACADVL gene (nucleotides 388-390), resulting in deletion of glu130 (E130X). In another patient, Souri et al. (1996) found the 3-bp deletion mutation in compound heterozygosity with the K382Q mutation (609575.0008).
In an infant with VLCAD deficiency (201475), Souri et al. (1996) found deletion of nucleotides 895-897 in the ACADVL gene, resulting in deletion of lys299 (K299X).
In an infant with VLCAD deficiency (201475), Souri et al. (1996) identified a 1144A-C transversion in the ACADVL gene, resulting in a lys382-to-gln (K382Q) substitution.
In a 42-year-old woman with late-onset VLCAD deficiency (201475), Smelt et al. (1998) identified compound heterozygosity for 2 mutations in the ACADVL gene: a G-to-A transition in exon 13, resulting in a gly401-to-asp (G401D) substitution, and a G-to-A transition in exon 14, resulting in an arg410-to-his (R410H; 609575.0010) substitution. The patient had recurrent rhabdomyolysis and markedly elevated levels of tetradecadienoic acid and hexadecadienoic acid.
For discussion of the G-to-A transition in exon 14 of the ACADVL gene, resulting in an arg410-to-his (R410H), that was found in compound heterozygous state in a patient with VLCAD deficiency by Smelt et al. (1998), see 609575.0009.
In an Israeli patient with VLCAD deficiency (201475), Watanabe et al. (2000) found homozygosity for a complex mutant allele with pro65-to-leu (P65L) and lys247-to-gln (K247Q) mutations in the ACADVL gene. The K247Q mutation resulted from a 937A-C transversion. The P65L mutation resulted in the skipping of exon 3. The nucleotide substitution causing the P65L amino acid change was a 194C-T transition located 11 bases upstream of the normal splice donor site of intron 3. This is an example of an exonic mutation that affects exon splicing; a similar situation had been described in the ACAT1 gene (see 203750.0009). RT-PCR showed 2 cDNA fragments of different sizes. One had the expected size and the other was shorter by 66 basepairs. In the case of P65L, the amino acid change did not reduce enzyme activity, whereas the K247Q mutation reduced it drastically.
In a patient with VLCAD deficiency (201475), Cox et al. (1998) identified a 1372T-C transition in the ACADVL gene, resulting in a phe458-to-leu (F458L) substitution.
In a 14-year-old Japanese girl with very mild manifestations of VLCAD deficiency (201475), Fukao et al. (2001) identified compound heterozygosity for 2 mutations in the ACADVL gene: 1 resulting in an ala416-to-thr (A416T) substitution, and the other resulting in an arg450-to-his (R450H; 609575.0014) substitution. In vitro functional expression studies showed that both mutant proteins retained residual activity at 30 degrees Celsius. Fukao et al. (2001) concluded that the temperature-sensitive mild mutations resulted in the milder phenotype in this patient.
For discussion of the arg450-to-his (R450H) substitution in the ACADVL gene that was found in compound heterozygous state in a Japanese patient with VLCAD deficiency by Fukao et al. (2001), see 609575.0013.
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