| *606761 | |||||||||||||||||||||||||||
| MALONYL-CoA DECARBOXYLASE; MLYCD | |||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||
| MCD | |||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: MLYCD | |||||||||||||||||||||||||||
| Cytogenetic location: 16q23.3 Genomic coordinates (GRCh37): 16:83,932,729 - 83,949,786 (from NCBI) | |||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||
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| TEXT | |||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||
| Malonyl-CoA decarboxylase (EC 4.1.1.9) catalyzes the conversion of malonyl-CoA to acetyl-CoA and carbon dioxide. It is thought to be involved in aspects of fatty acid biosynthesis and oxidation (Sacksteder et al., 1999). | |||||||||||||||||||||||||||
| Cloning | |||||||||||||||||||||||||||
| Malonyl-CoA decarboxylase is found most often in the liver, brain, heart, and skeletal muscle (Sacksteder et al., 1999). Gao et al. (1999) searched expressed sequence tag databases to identify human cDNAs with homology to the goose malonyl-CoA decarboxylase cDNA sequence. The 1,479-nucleotide human cDNA sequence is 70% identical to that of goose. FitzPatrick et al. (1999) identified a 2.1-kb human MCD cDNA encoding a 454-amino acid protein that shows 70.3% amino acid identity to goose Mcd. They found that the peptide sequence of the MCD enzyme contains a C-terminal peroxisomal targeting sequence (ser-lys-leu). This targeting sequence appeared to be functional in vivo, since the distribution of MCD enzymatic activity in rat liver homogenates, as measured by means of subcellular fractionation, strongly suggested that MCD was localized to peroxisomes in addition to mitochondria. To identify the human malonyl-CoA decarboxylase gene, Sacksteder et al. (1999) searched expressed sequence tag databases for sequences similar to that of goose malonyl-CoA decarboxylase, which contains the consensus sequence for the type 1 peroxisomal targeting signal (PTS1). | |||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||
| Gao et al. (1999) found that the intron/exon boundaries of the MLYCD gene are completely conserved in goose and human. | |||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||
| By radiation hybrid analysis, Sacksteder et al. (1999) mapped the MLYCD gene to 16q23-q24, between markers D16S422 and D16S402. Using mouse/human hybrid cell lines, Gao et al. (1999) mapped the malonyl-CoA decarboxylase gene to chromosome 16q24, in a 450-kb interval between D16S402 and D16S422. | |||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||
| Gao et al. (1999) identified a 4-bp deletion at the 3-prime end of exon 2 of the MLYCD gene (606761.0003) in homozygosity in a patient with malonyl-CoA decarboxylase deficiency (248360). By RT-PCR analysis of fibroblast RNA from 2 consanguineous Scottish patients with MCD deficiency reported by MacPhee et al. (1993), FitzPatrick et al. (1999) identified homozygous mutations in the MCD gene (606761.0002-606761.0003). Sacksteder et al. (1999) identified a 2-bp deletion (606761.0004) in a patient with severe malonicaciduria. By genomic sequencing of the MLYCD gene, Wightman et al. (2003) succeeded in identifying 16 of 18 pathogenic alleles in 9 unrelated patients with malonyl-CoA decarboxylase deficiency. Fibroblast cell lines were available from 8 of these patients and 2 previously reported patients with homozygous MLYCD mutations. Western blot analysis using antisera raised to a C-terminal peptide detected a 66-kD band that was absent in 6 patients and substantially reduced in 3 patients. One patient showed an increase in protein levels with a prominent 'smeary' 68- to 183-kD band. Immunocytochemical analysis of MLYCD-expressing patient cell lines showed apparent intracellular mislocalization. An extreme N-terminal mutation, gly3 to asp (606761.0005), mislocalized to the plasma membrane, suggesting that a novel targeting signal may reside in a 4-amino acid conserved N-terminal motif. Both a 25-base deletion (84-108del; 606761.0007) between the putative mitochondrial and peroxisomal initiating codons (M1 and M40) and a point mutation ablating the second of these (met40 to thr; 606761.0006) showed punctate perinuclear staining. As none of the 3 mislocalizing mutations were predicted to alter the catalytic function of the peptide, it seemed likely that correct subcellular localization of MLYCD is critical for its normal functioning. | |||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||
| An et al. (2004) showed that in rats fed a high-fat diet, whole-animal, muscle, and liver insulin resistance was ameliorated following hepatic overexpression of MCD, which decreased circulating free fatty acid (FFA) levels and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA, 2 candidate mediators of insulin resistance, were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, beta-OH-butyrate, in muscle of MCD-overexpressing animals. An et al. (2004) hypothesized that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle beta-OH-butyrate levels and improvement of insulin sensitivity. | |||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||
| .0001 MALONYL-CoA DECARBOXYLASE DEFICIENCY | |||||||||||||||||||||||||||
| MLYCD, SER148TER [dbSNP:rs104894528] | |||||||||||||||||||||||||||
| In a consanguineous Scottish patient with malonyl-CoA decarboxylase deficiency (248360) reported by MacPhee et al. (1993), FitzPatrick et al. (1999) identified a C-to-G transversion at nucleotide 442 of the MLYCD gene, resulting in a ser148-to-ter substitution in the N-terminal half of the protein. | |||||||||||||||||||||||||||
| .0002 MALONYL-CoA DECARBOXYLASE DEFICIENCY | |||||||||||||||||||||||||||
| MLYCD, IVS4AS, A-G, -14 | |||||||||||||||||||||||||||
| In a consanguineous Scottish patient with malonyl-CoA decarboxylase deficiency (248360) reported by MacPhee et al. (1993), FitzPatrick et al. (1999) identified an apparently homozygous A-to-G transition at position -14 in intron 4 of the MLYCD gene. The mutation created a novel 3-prime splice site within the intron, resulting in a 13-bp insertion in the mature RNA that caused a frameshift with predicted protein truncation. | |||||||||||||||||||||||||||
| .0003 MALONYL-CoA DECARBOXYLASE DEFICIENCY | |||||||||||||||||||||||||||
| MLYCD, 4-BP DEL, 638GTGA | |||||||||||||||||||||||||||
| In a patient with malonicaciduria, hypertrophic cardiomyopathy, and renal dysplasia as well as micropenis and hypotonia (248360), Gao et al. (1999) identified a 4-bp deletion at the 3-prime end of exon 2 of the malonyl-CoA decarboxylase cDNA. The deletion of GTGA beginning at nucleotide 638 was found in homozygosity in this patient; both of his parents were carriers. | |||||||||||||||||||||||||||
| .0004 MALONYL-CoA DECARBOXYLASE DEFICIENCY | |||||||||||||||||||||||||||
| MLYCD, 2-BP DEL, 947TT | |||||||||||||||||||||||||||
| In a patient with severe malonyl-CoA decarboxylase deficiency (248360), Sacksteder et al. (1999) identified a deletion of 2 T residues at nucleotides 947 and 948 of the MLYCD cDNA. A second mutation was not identified. | |||||||||||||||||||||||||||
| .0005 MALONYL-CoA DECARBOXYLASE DEFICIENCY | |||||||||||||||||||||||||||
| MLYCD, GLY3ASP [dbSNP:rs121908081] | |||||||||||||||||||||||||||
| In a patient reported by Brown et al. (1984) with MLYCD deficiency (248360), Wightman et al. (2003) found a G-to-A transition at nucleotide 8 of the cDNA predicted to result in a gly3-to-asp (G3D) protein change; the mutation was present in homozygous state. The MLYCD protein was mislocalized to the plasma membrane, suggesting that a novel targeting signal may reside in a 4-amino acid conserved N-terminal motif. | |||||||||||||||||||||||||||
| .0006 MALONYL-CoA DECARBOXYLASE DEFICIENCY | |||||||||||||||||||||||||||
| MLYCD, MET40THR [dbSNP:rs28937908] | |||||||||||||||||||||||||||
| In a patient reported by Matalon et al. (1993) with MLYCD deficiency (248360), Wightman et al. (2003) found homozygosity for a 119T-C transition in homozygous form predicted to result in an met40-to-thr (M40T) missense mutation in the protein. Immunocytochemistry in the patient's cells showed MLYCD to be localized to the perinuclear region of the cells. The fact that the patient had 25% enzyme activity but had a severe phenotype with cardiomyopathy showed that normal processing and targeting is necessary for MLYCD function (as outlined by Wightman et al. (2003)), other interpretations of the nature of the mutation in this case had been suggested by other workers. | |||||||||||||||||||||||||||
| .0007 MALONYL-CoA DECARBOXYLASE DEFICIENCY | |||||||||||||||||||||||||||
| MLYCD, 25-BP DEL, NT84 | |||||||||||||||||||||||||||
| In a patient reported by Yano et al. (1997) with MLYCD deficiency (248360), Wightman et al. (2003) identified a 25-bp deletion (84-108del) in homozygous state. The deletion was located between the putative mitochondrial and peroxisomal initiating codons (M1 and M40). The protein on immunohistochemical study showed punctate perinuclear staining, as in the case of the M40T mutation (606761.0006), which also showed ablation of the M40 peroxisomal initiating codon. | |||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||
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