Human Molecular Genetics, 2001, Vol. 10, No. 12 1299-1306
© 2001 Oxford University Press
Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency
Ludwig-Maximilians-University, Dr von Hauner Children’s Hospital, Department of Clinical Chemistry and Biochemical Genetics, Lindwurmstrasse 4, D-80337 Munich, Germany, 1University of California, San Diego, Department of Pediatrics, Biochemical Genetics Laboratory, 220 Dickinson Street, CA 92103, USA and 2University of Münster, Klinik und Poliklinik für Kinderheilkunde, Albert-Schweitzer-Strasse 33, D-48149 Münster, Germany
Received 14 February 2001; Revised and Accepted 11 April 2001.
DDBJ/EMBL/GenBank accession nos AF 261884 and AF 297332.
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ABSTRACT |
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3-Methylcrotonyl-CoA: carboxylase (EC 6.4.1.4; MCC) deficiency is an inborn error of the leucine degradation pathway (MIM *210200) characterized by increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. The clinical phenotypes are highly variable ranging from asymptomatic to profound metabolic acidosis and death in infancy. Sequence similarity with Glycine max and Arabidopsis thaliana genes encoding the two subunits of MCC permitted us to clone the cDNAs encoding the
- and ß-subunits of human MCC. The 2580 bp MCCA cDNA encodes the 725 amino acid biotin-containing -subunit. The MCCA gene is located on chromosome 3q26–q28 and consists of 19 exons. The 2304 bp MCCB cDNA encodes the non-biotin-containing ß-subunit of 563 amino acids. The MCCB gene is located on chromosome 5q13 and consists of 17 exons. We have sequenced both genes in four patients with isolated biotin-unresponsive deficiency of MCC. In two of them we found mutations in the MCCA gene. Compound heterozygosity for a missense mutation (S535F) and a nonsense mutation (V694X) were identified in one patient. One heterozygous mutation (S535F) was found in another patient. The remaining two patients had mutations in the MCCB gene. One consanguineous patient was homozygous for a missense mutation (R268T). In the other we identified a missense mutation in one allele (E99Q) and allelic loss of the other. Mutations were correlated with an almost total lack of enzyme activity in fibroblasts. These data provide evidence that human MCC deficiency is caused by mutations in either the MCCA or MCCB gene. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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3-Methylcrotonyl-CoA: carboxylase [3-methylcrotonoyl-CoA: carbon dioxide ligase (ADP-forming), EC 6.4.1.4; MCC] is an enzyme involved in the breakdown of the branched chain amino acid leucine. The reaction utilizes adenosine triphosphate (ATP) and bicarbonate, and the product is 3-methylglutaconyl-CoA (1). Human MCC deficiency (MIM *210200) is transmitted as an autosomal recessive trait. Biochemically it is characterized by the accumulation of 3-methylcrotonyl-CoA which leads to increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. In addition, accumulated acyl-CoA compounds are trans-esterified to acylcarnitine esters within the mitochondria; 3-hydroxyisovalerylcarnitine is the major abnormal metabolite and is found in blood and urine (2,3). The underlying genetic basis of this disease had not been elucidated previously. The clinical phenotypes are highly variable ranging from asymptomatic to profound metabolic acidosis and death in infancy (4–6). Patients have been reported in whom neurological manifestations developed in the first two years of life along with severe carnitine deficiency, hypoglycemia, ketoacidosis and hyperammonemia following intercurrent illness (7,8). Additional manifestations include feeding difficulty, failure to thrive, muscular hypotonia, seizures and psychomotor retardation (9–11). Treatment consists of restriction of dietary protein, supplementation with carnitine, and fluid and electrolyte therapy for acute episodes of acidosis. The disease was first recognized by Eldjarn et al. (12). MCC is localized within the mitochondrion (13) as one of three biotin-dependent carboxylases; the others are pyruvate: carboxylase and propionyl-CoA: carboxylase. No patient with isolated MCC deficiency has to date been responsive to biotin. Gompertz et al. (14) first measured directly diminished enzyme activity in patients. The bovine MCC holoenzyme has been identified as a tetramer of dissimilar
- and ß-subunits (15,16). The Glycine max MCCA gene encoding the biotin-containing -subunit (17) and the Arabidopsis thaliana MCCB gene encoding the non-biotin-containing ß-subunit (18) were cloned recently. Here we report the cloning of the human MCCA and MCCB cDNAs, the molecular characterization of the corresponding genes and the identification of mutations in each of these genes in biochemically proven patients with isolated deficiency of MCC. |
RESULTS |
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Cloning and characterization of MCCA
The human 2580 bp MCCA cDNA was cloned by sequence similarity to the G.max MCC
gene; the amino acid sequence encodes the 725 amino acid -subunit, which has a calculated molecular weight of 80.5 kDa. The protein is highly conserved between G.max and man (45% amino acid identity). Structure prediction algorithms (PhD, EMBL) failed to identify transmembrane helices and predict a soluble protein. Fluorescence in situ hybridization (FISH) analysis of metaphase chromosomes employing P1-derived artificial chromosome (PAC) clones confirmed the presence of the MCCA gene and demonstrated its cytogenetic position on chromosome 3q26–q28 (Fig. 1). The gene consists of 19 exons (Fig. 2A). Intron sizes have not been fully determined.
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Cloning and characterization of MCCB
The human 2304 bp MCCB cDNA was cloned by sequence similarity to the A.thaliana gene; the MCCß amino acid sequence encodes the ß-subunit of 563 amino acids which has a calculated molecular weight of 61.3 kDa. The protein is highly conserved between A.thaliana and man (58% amino acid identity). As in the case of MCC
, structure prediction algorithms (PhD, EMBL) failed to identify transmembrane helices and predict a soluble protein. A cleavage site for mitochondrial targeting pre-sequences (19) was identified at position 23 (PRA/YH) using the pSORT targeting prediction algorithm (http://psort.nibb.ac.jp/). FISH located the MCCB gene on chromosome 5q13 (Fig. 1). It consists of 17 exons (Fig. 2D). The cytogenetic location identified is consistent with a sequence-tagged site (STS) entry corresponding to exon 17 (GenBank accession no. G25331) positioned at 247.2 cR from the top of chromosome 5.
Biochemical characterization
In all four patients the diagnosis of MCC deficiency was made on the basis of urinary organic acid analysis by gas chromatography/mass spectrometry and of blood acylcarnitine analysis by electrospray tandem mass spectrometry. Each had markedly increased urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. The acylcarnitine profile revealed highly elevated concentrations of 3-hydroxyisovalerylcarnitine and an increased ratio of this compound to propionylcarnitine (Table 1). In three patients the diagnosis was confirmed by assay of the enzyme in cultured fibroblasts. Each patient studied showed zero or minimal residual activity of the holoenzyme. To rule out a potential multiple carboxylase deficiency (holocarboxylase: synthetase deficiency; MIM *253270 or biotinidase deficiency; MIM *253260) propionyl CoA: carboxylase, pyruvate: carboxylase, and biotinidase were shown to be normal. Biochemical characterization does not permit differentiation between defects located in the MCCA or MCCB gene.
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Mutational analysis
Sequences from exon-flanking intronic regions from all of the exons of MCCA and MCCB were determined by searching unfinished sequences of the published databases, direct sequencing of PAC-DNA using exon-derived oligonucleotides or sequencing of exon–exon PCR products from either end. Furthermore, the complete coding regions of both genes were RT–PCR-amplified in a single reaction. Oligonucleotide primer sequences are given in Table 2.
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Mutational analysis of genomic DNA was performed by PCR-amplification of all of the coding exons and sequencing of the products from either end. RNA-based analysis was done by amplification of the full coding region of the cDNA and sequencing with internal exonic oligonucleotide primers.
Sequencing the complete coding regions of MCCA and MCCB of our MCC-deficient patients revealed two individuals with mutations in the MCCA and two in the MCCB gene. Patient MA was found to be a compound heterozygote for a missense mutation (1604C
T; S535F) and a nonsense mutation (del2079A; V694X) in MCCA (Fig. 2B), and this was confirmed by segregation analysis. In patient KF we identified a heterozygous MCCA missense mutation (1604CT; S535F) (Fig. 2C). Sequencing the entire coding region, the expected defect of the other allele remained cryptic. In patient LM we found a missense mutation in MCCB (295GC; E99Q) that appeared homozygous on mRNA analysis, but heterozygous on genomic analysis (Fig. 2E). Compound heterozygosity for E99Q and a cryptic mutation (possibly in the promoter region) causing allelic loss was concluded. KK, the second MCCB patient, displayed homozygosity for a missense mutation (803GC; R268T) consistent with his parental consanguinity (Fig. 2F). The data are summarized in Table 1.
The S535F mutation identified in MCCA in two unrelated patients represents a significant amino acid substitution (exchange of a hydrophilic residue by a highly hydrophobic one), although it is not positioned in a region conserved between G.max and human MCCA. Additional sequence analysis confirmed that the 1604CT mutation was absent from 50 unrelated healthy individuals (data not shown). The V694X MCCA mutation leads to premature termination of the conserved biotin-carrier domain such that the hydrophobic residue critical for biotinylation (F714) is not expressed. In all patients of whom fibroblast cultures were available (including the MCCB defective patient LM) the presence of MCC could be demonstrated in a mitochondrial fraction by the detection of avidin-binding proteins (data not shown). In MCCB the glutamic acid residue at position 99 (mutated to glutamine in patient LM) represents an amino acid residue fully conserved in the genes of man, mouse (GenBank EST accession no. AA275644), A.thaliana, Caenorhabditis elegans (GenBank accession no. P34385) and Drosophila melanogaster (GenBank accession no. AF57388). The same residue is also found in carboxyltransferase subunits of other biotin-containing enzymes such as propionyl-CoA: carboxylases and acetyl-CoA: carboxylases from various species. In addition, a recent report describing the cloning of the MCCA and MCCB genes (20) independently found the E99Q mutation in MCCB in two unrelated families. In that study, expression of this allele did not lead to the restoration of enzyme activity in an MCCB defective cell line. The MCCB arginine residue at position 268 (mutated to threonine in patient KK) is positioned within the conserved carboxylase domain and appears to be identical in mouse and man, but not in A.thaliana. This amino acid exchange does not represent a frequent polymorphism as determined by PmlI restriction analysis of 100 normal chromosomes. The mutation could impair MCC function by itself or it could alter splicing significantly, since the mutation affects the conserved most 3'-positioned guanine residue of an exon (exon 8).
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DISCUSSION |
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The composition of the MCC holoenzyme and its non-identical subunit structure had long been known from studies of the enzyme isolated from bovine kidney (15,16). The recent cloning of G.max MCCA and A.thaliana MCCB encoding the
- and ß-subunits of the holoenzyme, in conjunction with the high conservation between plant and human MCC genes, has enabled us to identify the human orthologs. The corresponding proteins are predicted to be soluble and located within the mitochondrial matrix. The two subunits, encoded by genes on different chromosomes, do not exhibit any sequence similarity to one another but are highly conserved between plants and humans.
The C-terminus of MCC contains the biotin-carrier domain shared among biotin-carrier proteins of different enzymatic functions (17). It is centered on the conserved biotinylation site Ala-Met-Lys-Met (amino acids 679–683) (21), where the lysine residue is biotinylated (22). We found this motif fully conserved between G.max and man. In addition, a hydrophobic residue 33 amino acids downstream from the lysine residue (phenylalanine in human MCC) appears to be essential for biotinylation (23). The N-terminal region contains the conserved biotin carboxylase domain (17) that most likely catalyzes the ATP-dependent carboxylation of biotin, the first half-reaction of MCC. The positions 209–214 appear to represent the ATP-binding site and are fully conserved between soybean and man. Human MCCß shows sequence similarity to carboxyltransferase subunits of biotin-containing enzymes such as methylmalonyl-CoA: carboxylase, propionyl-CoA: carboxylase and transcarboxylase (the substrates of which all share a methyl branch) as described for A.thaliana MCCß by McKean et al. (18).
These features identify the genes cloned as the human orthologs of MCCA and MCCB. Since two different genes contribute to MCC composition and function, we had hypothesized the disease to be genetically heterogeneous in the sense that defects in either MCCA or MCCB could lead to compromised MCC function. Sequencing of both genes in our MCC-deficient patients revealed two patients defective in MCCA and two with defects of MCCB. The mutations identified show features that permit the prediction of functional significance in conjunction with the biochemical data. The analysis of characteristically elevated metabolites is a powerful diagnostic tool but, as in the case of the direct measurement of MCC activity, it does not distinguish between defects in MCCA and MCCB. In the future complementation studies involving fusion with genetically defined cell lines or, alternatively, MCCA or MCCB wild-type cDNA transfection should be able to allocate patients to defects in MCCA or MCCB prior to DNA sequencing.
Our report confirms the reports on the molecular basis of human MCC deficiency, which have been published very recently (20,24). The MCCA and MCCB cDNA sequences, chromosomal localization and gene structures reported are identical to our data. Overall, six mutant alleles were described in the MCCA gene [two mutant alleles by Gallardo et al. (24) and five mutant alleles by Baumgartner et al. (20) with one identical missense mutation (R385S) in exon 11]. In the MCCB gene 13 mutant alleles were reported [four mutant alleles by Gallardo et al. (24) and nine mutant alleles by Baumgartner et al. (20) with no overlap]. In our study, two novel mutations in each of the MCCA and MCCB genes were discovered, while we found the same missense mutation E99Q as Baumgartner et al. (20). The combined data to date do not permit genotype–phenotype correlation. Even the absence of one of the MCC subunits in conjunction with completely missing enzyme activity does not necessarily lead to any clinical manifestations. In our study, in both MCCA patients and in one MCCB patient of whom appropriate material was available the MCC protein was present. The technique using an avidin alkaline phosphatase conjugate in protein fractions enriched for mitochondria was not able to allow the detection of a possibly reduced amount of protein.
MCC deficiency has been considered until recently to be a rare inborn error of metabolism. Asymptomatic patients have been identified after the disorder was recognized in a symptomatic sibling (4). Since many patients have remained well with modest protein restriction despite continued abnormal organic aciduria, the prognosis has appeared generally good, especially if the diagnosis is made before the first profound metabolic decompensation. The fact that an increasing number of screening centers have implemented an extended prospective newborn screening program using tandem mass spectrometry has allowed the early detection of organic acidemias such as MCC deficiency. Surprisingly, our data and data from other newborn screening centers indicate that MCC deficiency may be the most frequent organic acidemia (25–28). The unexpectedly high incidence implies that many of those with this disorder are devoid of pathologic features and usually remain undetected (29). Even though these individuals, like most newborns, are asymptomatic, they are at risk of the development of acute episodes of potentially life-threatening metabolic decompensation or permanent neurological damage precipitated by protein overload or catabolic events such as intercurrent infectious disease, fasting or surgery. The considerable heterogeneity in the severity of clinical presentation indicates that there should be individual treatment protocols. Early identification of a high number of individuals with MCC deficiency in the course of newborn screening and systematic genetic characterization may help to evaluate the phenotype, to develop optimal treatment protocols and to preserve an excellent prognosis. Secondary genetic or environmental factors yet to be defined may play an important role in determining phenotypic variation and the long-term outcome of the disease.
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MATERIALS AND METHODS |
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Patients
Informed consent was obtained from the parents of all patients included in the study. Patient LM (5.5 years of age) was diagnosed by the analysis of urinary organic acids at the age of 3, when he developed seizures following an intercurrent infectious disease. Besides slight deficits in his fine motor skills the neurological examinations and developmental assessments were normal. Patients KF, KK and MA (1.5, 1.5 and 0.8 years of age, respectively) were found through newborn screening by elevated concentrations of 3-hydroxyisovalerylcarnitine (Table 1) and remained completely asymptomatic. Patients KF and KK were products of consanguineous mating. None of the patients responded to biotin. They have all been treated with modest restriction of protein intake and supplementation with carnitine. A major element in management remains the avoidance of fasting.
cDNA cloning
Using the BLAST algorithm (30) we searched the public databases for human expressed sequence tags (ESTs) encoding proteins similar to the amino acid sequence of the -subunit of the G.max MCC [GenBank accession no. AAA531430.1 (17)] and of the ß-subunit of A.thaliana [GenBank accession no. AAF 35259 (18)]. We identified such ESTs (MCC-A: GenBank accession nos AW410916, AA337013, AA336949, AW516000; MCC-B: GenBank accession nos AW410917, R88931, AA465612) and deduced oligonucleotide primers to amplify cDNA fragments by RT–PCR from human fibroblast mRNA. These fragments were cloned and sequenced using the fluorescent didesoxy dye-terminator technology. 5' rapid amplification of cDNA ends (RACE) using an adaptor-ligated human liver cDNA library (Clontech) was performed to obtain missing 5' cDNA fragments.
Determination of the gene structures
BLAST searches of preliminary sequences from the human genome project using MCCA and MCCB cDNA probes identified genomic sequence fragments containing portions of the MCCA and MCCB genes. All exons and exon–intron-flanking sequences were obtained for the MCCB gene from GenBank (accession no. AC026775) containing chromosome 5 genomic contigs, whereas intron sizes were not fully available. Corresponding analyses revealed only fragments of the MCCA gene. GenBank accession no. AC026920 contained chromosome 3 contigs representing most of the MCCA gene but these sequence data were not sufficient to amplify all coding exons from genomic DNA samples. A human genomic PAC library (31) was screened using (-32P) dATP labeled MCCA or MCCB cDNA at the Resource Center of the German Human Genome Project, Berlin (32). Of two PAC clones identified, both contained the entire MCCA gene confirmed by PCR for the 5' and 3' ends (clone nos: RPCIP704D13172Q2A and RPCIP704E15342Q2). Three clones identified contained the entire MCCB gene as determined by PCR (clone nos: RPCIP704B17566Q2, RPCIP704E10726Q2 and RPCIP704F15978Q2). PAC-DNA was isolated from these clones by ion exchange chromatography and used to confirm the gene structure by exon–exon-PCR followed by DNA sequencing from either end or direct sequencing of PAC-DNA using exon-derived oligonucleotide primers.
FISH analyses
Human metaphase cells were prepared from phytohemagglutinin-stimulated peripheral blood lymphocytes according to standard procedures. FISH analysis was performed using MCCA and MCCB PAC-DNA labeled with biotin-14-dUTP (Life Technologies) by nick-translation and pre-annealed with Cot-1 DNA (Life Technologies). Detection and visualization were achieved using the avidin-fluorescein isothiocyanate/antiavidin antibody system described elsewhere (33,34). Chromosomes were identified by staining with 4,6-diamino-2-phenylindole dihydrochloride (DAPI).
Mutational analyses
Analysis of patient material was performed from blood leukocyte genomic DNA or skin fibroblast RNA samples. Details of the amplification procedures are listed in Table 2. Genomic fragment PCR amplifications employed Taq polymerase (Roche) and large fragment PCR amplification (cDNA amplification and exon–exon-PCR) was performed using the Expand High Fidelity System (Roche). The complete coding regions of the MCCA and MCCB genes could be amplified by one RT–PCR reaction each. Since RNA was not available from all patients we established genomic DNA analysis for both genes. All coding exons of MCCA and MCCB genes could be PCR-amplified using standard PCR conditions and oligonucleotide primers derived from exon-flanking intronic sequences (Table 2).
Metabolite analyses and enzyme assays
Urinary organic acid analysis was done using a modification of the method of Hoffmann et al. (35) by capillary gas chromatography of trimethylsilyl esters and O-(2,3,4,5,6-pentafluorobenzyl)oximes of oxoacids formed after ethyl acetate extraction. Metabolites were identified on the basis of their retention time and confirmed by mass spectrometry. Quantitative analysis of blood acylcarnitines was performed by electrospray tandem mass spectrometry (ESI-MS/MS) using a modification of the method of Chace et al. (36). The assays for propionyl CoA: carboxylase, 3-methylcrotonyl CoA: carboxylase and pyruvate: carboxylase involve the incorporation of [14C] bicarbonate (NaH [14C]O3) into the appropriate substrate to give labeled non-volatile products. Excess of labeled bicarbonate is removed by acidification by formic acid. These methods have been described previously (37–39).
MCC detection
To detect the biotin-containing MCC-subunit a fraction enriched for mitochondrial proteins was prepared from cultured patient and normal fibroblasts as described by Old and De Vivo (40). The proteins were separated by SDS–PAGE and blotted to a nitrocellulose membrane. Detection was achieved with an avidin alkaline phosphatase conjugate (Biorad) using a 1:5000 dilution and a standard chemoluminescent assay system.
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FOOTNOTES |
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+ These authors contributed equally to this work
To whom correspondence should be addressed. Tel: +49 89 5160 2805; Fax: +49 89 5160 3320; Email: holzinger@kk-i.med.uni-muenchen.de
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