The Molecular Basis of Malonyl-CoA Decarboxylase Deficiency

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The Molecular Basis of Malonyl-CoA Decarboxylase Deficiency David R. FitzPatrick, Alison Hill, John L. Tolmie, David R. Thorburn, John Christodoulou The American Journal of Human Genetics Volume 65, Issue 2, Pages 318-326 (August 1999) DOI: 10.1086/302492 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 Alignment of the predicted hMCDp (GenBank AF097832) and gMCDp (GenBank P12617) sequences by use of ClustalW interactive analysis program (ClustalW). This shows 70.3% identity of >454 amino acids. The two characterized initiating methionines of the goose peptide are shown in boldface type (position 1 and 50). C-terminal peroxisomal-targeting sequences were identified in both human and goose sequences (-SKL) and are underlined. An ORF predicting a 360–amino acid peptide (GenBank Z46242) from a C. elegans gene (labeled “Nematode”) from chromosome III also showed a high degree of homology on searching and is likely to be orthologous. There was 35.8% sequence identity among all three peptides. The American Journal of Human Genetics 1999 65, 318-326DOI: (10.1086/302492) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 Case 1 mutation. A, Electrophoresis of RT-PCR products from the patients in case 2 (lane 1) and in case 1 (lane 2) and from the controls (lanes 3–6), with use of primer pair MCD3 with silver-stained SSCP (top) and primers MCD4F and MCD3R (predicted normal product size of 105 bp) with ethidium bromide–stained agarose gel analysis (bottom). Both analyses show a larger fragment in case 1, with no evidence of a normal band. B, Sequence of genomic PCR product from the patient in case 1 and a normal control showing A→G at position −14 in intron 4 (IVS4 –14A→G). The larger fragment shown in A was due to the creation of a novel 3′ splice site within the intron, thus creating the 13-bp insertion in the cDNA (CCATGCTTTACAG), as detailed in the two bottom panels. C, 2% agarose gel electrophoresis of MSPCR products by means of primer-set MCD8, showing appropriate segregation of the mutation within the nuclear family of the patient in case 1 (lane 4), homozygous mutant larger band (113 bp) for patients with both parents heterozygous (lanes 2 and 3), and a normal control homozygous smaller band (93 bp, lane 5). The DNA size marker ladder (L) shows 100-bp (lower) and 200-bp (upper) bands in lane 1. The American Journal of Human Genetics 1999 65, 318-326DOI: (10.1086/302492) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 Case 2 mutation. Sequences of RT-PCR product from patient in case 2 and a healthy control show an apparently homozygous C→G transversion at nucleotide 442 in the cDNA, denoted by an asterisk (*). This results in the change of a serine codon (TCA) to a stop codon (TGA) at position 148 in the peptide (S148X). The American Journal of Human Genetics 1999 65, 318-326DOI: (10.1086/302492) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 4 Marker-enzyme studies of rat liver organelle fractions. Enzyme activities were assayed in duplicate. The means of the specific activities are plotted for each organellar fraction. Abbreviations: homog. = homogenate; mito. = mitochondrial fraction; micro. = microsomal fraction; perox. = peroxisomal fraction; and super. = supernatant. The American Journal of Human Genetics 1999 65, 318-326DOI: (10.1086/302492) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 5 pH studies of rat liver mitochondrial and peroxisomal preparations. MCD activity was assayed in duplicate. The means of the specific activities are plotted for each organellar fraction. Two peaks—one at pH ∼4.5–5.0 and the second at pH ∼8.0–8.5—could be identified for both preparations. The American Journal of Human Genetics 1999 65, 318-326DOI: (10.1086/302492) Copyright © 1999 The American Society of Human Genetics Terms and Conditions