Alternative titles; symbols
HGNC Approved Gene Symbol: DDC
SNOMEDCT: 124600004; ICD10CM: E70.81;
Cytogenetic location: 7p12.2-p12.1 Genomic coordinates (GRCh38) : 7:50,458,442-50,565,405 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p12.2-p12.1 | Aromatic L-amino acid decarboxylase deficiency | 608643 | Autosomal recessive | 3 |
DOPA decarboxylase (EC 4.1.1.28) is an enzyme implicated in 2 metabolic pathways, synthesizing 2 important neurotransmitters, dopamine and serotonin (Christenson et al., 1972). Following the hydroxylation of tyrosine to form L-dihydroxyphenylalanine (L-DOPA), catalyzed by tyrosine hydroxylase (TH; 191290), DDC decarboxylates L-DOPA to form dopamine. This neurotransmitter is found in different areas of the brain and is particularly abundant in basal ganglia. Dopamine is also produced by DDC in the sympathetic nervous system and is the precursor of the catecholaminergic hormones, noradrenaline and adrenaline in the adrenal medulla. In the nervous system, tryptophan hydroxylase (191060) produces 5-OH tryptophan, which is decarboxylated by DDC, giving rise to serotonin. DDC is a homodimeric pyridoxal 5-prime phosphate (PLP)-dependent enzyme. Ichinose et al. (1989) prepared a cDNA clone for the coding region of human aromatic L-amino acid decarboxylase by screening a human pheochromocytoma cDNA library with an oligonucleotide probe that corresponded to a partial amino acid sequence of the enzyme purified from the tumor. The cDNA clone encoded a protein of 480 amino acids, with a calculated molecular mass of 53.9 kD. The amino acid sequence asn-phe-asn-pro-his-lys-trp around a possible pyridoxal phosphate cofactor binding site was shown to be identical in human, Drosophila, and pig enzymes. The protein encoded by hepatoma cells is the same as that encoded by adrenal chromaffin-derived pheochromocytoma cells.
Sumi-Ichinose et al. (1992) showed that the DDC gene has 15 exons spanning more than 85 kb and exists as a single copy in the haploid genome. The boundaries between exons and introns followed the AG/GT rule. The sizes of exons and introns ranged from 20 to 400 bp and from 1.0 to 17.7 kb, respectively. Untranslated regions located in the 5-prime region of mRNA were encoded by exons 1 and 2.
By hybridization of a cDNA probe to somatic cell hybrid DNAs, Bruneau et al. (1990) concluded that the DDC gene is located on chromosome 7. Scherer et al. (1992) confirmed the localization of the DDC gene to chromosome 7 using a new panel of somatic cell hybrids. They localized the gene to 7p11 by fluorescence in situ hybridization (FISH). Sumi-Ichinose et al. (1992) mapped the gene to 7p12.3-p12.1 by fluorescence in situ hybridization. By isotopic in situ hybridization, Craig et al. (1992) localized the DDC gene to 7p13-p11, with the largest concentration of grains in 7p12.
De Luca et al. (2003) found that variation in the dopa decarboxylase gene is related to longevity in Drosophila. They pointed out that Ddc is only one of the enzymes in the biosynthetic pathways for bioamines and catecholamines. A polymorphism in tyrosine hydroxylase (TH; 191290), the rate-limiting enzyme in the synthesis of catecholamines, is associated with variation in human longevity (De Benedictis et al., 1998; De Luca et al., 2001).
To examine putative central and peripheral sources of embryonic brain 5-HT (serotonin), Bonnin et al. (2011) used Pet1 (FEV; 607150)-null mice in which most dorsal raphe neurons lack 5-HT. They detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, Bonnin et al. (2011) investigated the nature of this exogenous source and uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. The mouse placenta expresses both Tph1 (191060) and Aadc in the syncytiotrophoblastic cell layer at embryonic days 10.5 through 14.5. Human placental fetal villi at 11 weeks' gestation showed robust 5-HT neosynthesis, indicating that a placental source of 5-HT is important for human fetal development. Bonnin et al. (2011) concluded that their study revealed a new, direct role for placental metabolic pathways in modulating fetal brain development and indicated that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.
In 6 patients with AADC deficiency (AADCD; 608643), Chang et al. (1998) identified 6 mutations in the AADC gene (107930.0001-107930.0006).
Pons et al. (2004) identified 5 novel mutations in the AADC gene in patients with AADC deficiency.
Among 49 patients with genetically confirmed AADC deficiency, Brun et al. (2010) reported 24 different mutations in the AADC gene, including 8 novel mutations. A splice site mutation (IVS6+4A-T; 107930.0007) was by far the most common mutation with an allele frequency of 45%. All patients with the IVS6+4A-T mutation were of Chinese or Taiwanese origin or lived in Taiwan. Other common mutations included S250F (107930.0002), with an allele frequency of 10%, and G102S (107930.0001), with an allele frequency of 8%.
In a 5-year-old boy with AADC deficiency, Montioli et al. (2019) identified compound heterozygous mutations in the AADC gene (A91V, 107930.0005 and C410G, 107930.0008). The mutations were identified by direct gene sequencing. Montioli et al. (2019) expressed A91V and C410G AADC mutant homodimers in E. coli and found that both showed decreased PLP binding affinity. The C410G mutant had a 4-fold decrease in catalytic efficiency, whereas the A91V mutant had a 1,300-fold decrease in catalytic efficiency and altered both the protein tertiary structure and coenzyme microenvironment. In addition, an A91V/C410G heterodimer constructed via a dual-vector prokaryotic expression strategy showed decreased catalytic activity compared to the catalytic activity of either mutant homodimer, indicating a potential negative complementation effect.
Himmelreich et al. (2019) reviewed the 79 disease-causing mutations reported in the DDC locus-specific database (Pediatric Neurotransmitter Diseases database, PNDdb), which included 58 missense, 9 splice site, 6 frameshift, 1 in-frame, 3 complex, and 2 nonsense mutations. Fourteen mutations were predicted to affect catalytic loop 1 of the DDC protein, 4 were predicted to impair PLP binding, and 2 synonymous mutations were predicted to lead to abnormal splicing.
Using an E. coli expression system, Longo et al. (2021) examined the effects on enzyme structure and function of mutant AADC homodimers and heterodimers resulting from homozygous (T69M, S147R (107930.0004), M362T) or compound heterozygous (T69M/S147R; C281W/M362T) mutations in the DDC gene. The AADC T69M homodimer had about 11% catalytic efficiency and the AADC S147R homodimer had 0.001% catalytic efficiency. The AADC T69M/S147R heterodimer had 0.18% activity, despite being more stable than either homodimer, suggesting a negative complementation effect. The AADC C281W homodimer could not be assessed as a homodimer due to poor solubility, and the AADC M362T homodimer had 35% catalytic activity compared to wildtype. The C281W/M362T heterodimer was less stable than the M362T heterodimer but had 34% catalytic activity compared to wildtype. Longo et al. (2021) concluded that if mutation in the DDC gene directly affects the AADC active site, it will cause more functional damage than does a mutation affecting protein folding. This may explain why a patient (patient 1, previously reported as patient 3 in Manegold et al., 2009) with AADC deficiency and a homozygous T69M mutation in the DDC gene had a milder phenotype compared to a patient (patient 2, previously reported as patient 6 in Manegold et al., 2009) with AADC deficiency and compound heterozygous mutations (T69M and S147R) in the DDC gene.
Association with Nicotine Dependence
Ma et al. (2005) tested 8 SNPs within DDC for association with nicotine dependence (ND), which was assessed by smoking quantity (SQ), heaviness of smoking index (HSI), and the Fagerstrom test for ND (FTND) score, in a total of 2,037 smokers and nonsmokers from 602 nuclear families of African American or European American ancestry. Association analysis for individual SNPs indicated that rs921451 was significantly associated with 2 of the 3 adjusted ND measures in European Americans. Haplotype-based association analysis revealed a protective T-G-T-G haplotype for rs921451-rs3735273-rs1451371-rs2060762 in African Americans, which was significantly associated with all 3 adjusted ND measures after correction for multiple testing. In contrast, Ma et al. (2005) found a high-risk T-G-T-G haplotype for a different SNP combination in European Americans, rs921451-rs3735273-rs1451371-rs3757472, which showed a significant association with the SQ and FTND score.
In a patient with AADC deficiency (AADCD; 608643), Chang et al. (1998) and Hyland et al. (1998) identified a homozygous G-to-A transition in exon 3 of the AADC gene, resulting in a gly102-to-ser (G102S) substitution. Expression studies showed that the mutant protein activity was 16% that of the wildtype protein. The mutant protein showed increased L-DOPA binding, suggesting that the region around residue 102 is critical for L-DOPA binding.
Among 49 patients with genetically confirmed AADC deficiency, Brun et al. (2010) found that the allele frequency of the G102S mutation was 8%.
In 1 patient with AADC deficiency (AADCD; 608643), Chang et al. (1998) identified a homozygous C-to-T transition in exon 7 of the AADC gene, resulting in a ser250-to-phe (S250F) substitution. In another patient with AADC deficiency, they found the S250F mutation in compound heterozygous state but did not identify the other mutation.
In monozygotic twin boys of Arab descent with AADC deficiency first reported by Hyland et al. (1992), Pons et al. (2004) identified homozygosity for the S250F mutation.
Among 49 patients with genetically confirmed AADC deficiency, Brun et al. (2010) found that the allele frequency of the S250F mutation was 10%.
In E. coli, Montioli et al. (2013) found that the specific activity and immunoreactivity of the S250F variant were 14% and 66%, respectively, of the wildtype enzyme, consistent with a partial loss of function. Although ser250 is not essential for the catalytic activity of the enzyme, the mutation caused a 7-fold reduction of catalytic activity and a conformational change that was transmitted to the active site. In vitro expression studies in CHO cells showed that the mutant protein was more susceptible to proteasomal degradation compared to wildtype. These findings indicated that the loss of function of S250F was due to 2 mechanisms affecting activity and folding. Treatment with 4-phenylbutyric acid or pyridoxine increased the expression level and the decarboxylase activity of mutant-expressing cells in a dose-dependent manner, suggesting that it may be of therapeutic value in patients with this mutation.
In a patient with AADC deficiency (AADCD; 608643), Chang et al. (1998) identified a homozygous T-to-C transition in exon 9 of the AADC gene, resulting in a phe309-to-leu (F309L) substitution.
In a patient with AADC deficiency (AADCD; 608643), Chang et al. (1998) identified a homozygous A-to-C transversion in exon 5 of the AADC gene, resulting in a ser147-to-arg (S147R) substitution.
In a patient with AADC deficiency (AADCD; 608643), Chang et al. (1998) identified a C-to-T transition in exon 3 of the AADC gene, resulting in an ala91-to-val (A91V) substitution. The patient was compound heterozygous for the A91V mutation and a G-to-A transition in exon 8 of the AADC gene, resulting in an ala275-to-thr (A275T; 107930.0006) substitution.
In a 5-year-old patient with AADC deficiency, Montioli et al. (2019) identified compound heterozygous mutations in the AADC gene: A91V and a c.1228T-G transversion resulting in a cys410-to-gly (C410G; 107930.0008) substitution at a highly conserved residue. The mutations were identified by direct gene sequencing. Montioli et al. (2019) expressed A91V and C410G AADC mutant homodimers in E. coli and found that both showed decreased PLP binding affinity. The C410G mutant had a 4-fold decrease in catalytic efficiency, whereas the A91V mutant had a 1,300-fold decrease in catalytic efficiency and altered both the protein tertiary structure and coenzyme microenvironment. In addition, an A91V/C410G heterodimer constructed via a dual-vector prokaryotic expression strategy showed decreased catalytic activity compared to the catalytic activity of either mutant homodimer, indicating a potential negative complementation effect.
For discussion of the ala275-to-thr (A275T) mutation in the AADC gene that was found in compound heterozygous state in a patient with AADC deficiency (AADCD; 608643) by Chang et al. (1998), see 107930.0005.
Brun et al. (2010) found that an A-to-T transversion in intron 6 (IVS6+4A-T) of the DDC gene was the most common mutant allele among 49 patients with AADC deficiency (AADCD; 608643), with an allele frequency of 45%. Seventeen patients were homozygous for the IVS6+4A-T mutation, and 6 patients were compound heterozygous for IVS6+4A-T and a missense mutation. All patients with the IVS6+4A-T mutation were of Chinese or Taiwanese origin or lived in Taiwan.
For discussion of the c.1228T-G transversion in the AADC gene, resulting in a cys410-to-gly (C410G) substitution, that was found in compound heterozygous state in a patient with AADC deficiency (AADCD; 608643) by Montioli et al. (2019), see 107930.0005.
Bonnin, A., Goeden, N., Chen, K., Wilson, M. L., King, J., Shih, J. C., Blakely, R. D., Deneris, E. S., Levitt, P. A transient placental source of serotonin for the fetal forebrain. Nature 472: 347-350, 2011. [PubMed: 21512572] [Full Text: https://doi.org/10.1038/nature09972]
Brun, L., Ngu, L. H., Keng, W. T., Ch'ng, G. S., Choy, Y. S., Hwu, W. L., Lee, W. T., Willemsen, M. A. A. P., Verbeek, M. M., Wassenberg, T., Regal, L., Orcesi, S., and 13 others. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 75: 64-71, 2010. Note: Erratum: Neurology 75: 576 only, 2010. [PubMed: 20505134] [Full Text: https://doi.org/10.1212/WNL.0b013e3181e620ae]
Bruneau, G., Gross, M.-S., Krieger, M., Bernheim, A., Thibault, J., Nguyen, V. C. Preparation of a human DOPA decarboxylase cDNA probe by PCR and its assignment to chromosome 7. Ann. Genet. 33: 208-213, 1990. [PubMed: 1710430]
Chang, Y. T., Mues, G., McPherson, J. D., Bedell, J., Marsh, J. L., Hyland, K., Courtwright, K. H., Summers, J. W. Mutations in the human aromatic L-amino acid decarboxylase gene. (Abstract) J. Inherit. Metab. Dis. 21: 4 only, 1998.
Christenson, J. G., Dairman, W., Udenfriend, S. On the identity of DOPA decarboxylase and 5-hydroxytryptophan decarboxylase (immunological titration-aromatic L-amino acid decarboxylase-serotonin-dopamine-norepinephrine). Proc. Nat. Acad. Sci. 69: 343-347, 1972. [PubMed: 4536745] [Full Text: https://doi.org/10.1073/pnas.69.2.343]
Craig, S. P., Le Van Thai, A., Weber, M., Craig, I. W. Localisation of the gene for human aromatic L-amino acid decarboxylase (DDC) to chromosome 7p13-p11 by in situ hybridisation. Cytogenet. Cell Genet. 61: 114-116, 1992. [PubMed: 1395716] [Full Text: https://doi.org/10.1159/000133384]
De Benedictis, G., Carotenuto, L., Carrieri, G., De Luca, M., Falcone, E., Rose, G., Cavalcanti, S., Corsonello, F., Feraco, E., Baggio, G., Bertolini, S., Mari, D., Mattace, R., Yashin, A. I., Bonafe, M., Franceschi, C. Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2). Europ. J. Hum. Genet. 6: 534-541, 1998. [PubMed: 9887369] [Full Text: https://doi.org/10.1038/sj.ejhg.5200222]
De Luca, M., Rose, G., Bonafe, M., Garasto, S., Greco, V., Weir, B. S., Franceschi, C., De Benedictis, G. Sex-specific longevity associations defined by tyrosine hydroxylase-insulin-insulin growth factor 2 haplotypes on the 11p15.5 chromosomal region. Exp. Gerontol. 36: 1663-1671, 2001. Note: Erratum: Exp. Gerontol. 37: 607-608, 2002. [PubMed: 11672987] [Full Text: https://doi.org/10.1016/s0531-5565(01)00146-2]
De Luca, M., Roshina, N. V., Geiger-Thornsberry, G. L., Lyman, R. F., Pasyukova, E. G., Mackay, T. F. C. Dopa decarboxylase (Ddc) affects variation in Drosophila longevity. Nature Genet. 34: 429-433, 2003. [PubMed: 12881721] [Full Text: https://doi.org/10.1038/ng1218]
Himmelreich, N., Montioli, R., Bertoldi, M., Carducci, C., Leuzzi, V., Gemperle, C., Berner, T., Hyland, K., Thony, B., Hoffmann, G. F., Voltattorni, C. B., Blau, N. Aromatic amino acid decarboxylase deficiency: molecular and metabolic basis and therapeutic outlook. Molec. Genet. Metab. 127: 12-22, 2019. Note: Erratum: Molec. Genet. Metab. 134: 216 only, 2021. [PubMed: 30952622] [Full Text: https://doi.org/10.1016/j.ymgme.2019.03.009]
Hyland, K., Chang, Y. T., Arnold, L. A., Brautigam, C., Sharma, R. K., Hoffmann, G., Courtwright, K. H., Summers, J. W. Aromatic L-amino acid decarboxylase deficiency responsive to levodopa: identification of an active site glycine in exon three. (Abstract) J. Inherit. Metab. Dis. 21: 4 only, 1998.
Hyland, K., Surtees, R. A. H., Rodeck, C., Clayton, P. T. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 42: 1980-1988, 1992. [PubMed: 1357595] [Full Text: https://doi.org/10.1212/wnl.42.10.1980]
Ichinose, H., Kurosawa, Y., Titani, K., Fujita, K., Nagatsu, T. Isolation and characterization of a cDNA clone encoding human aromatic L-amino acid decarboxylase. Biochem. Biophys. Res. Commun. 164: 1024-1030, 1989. [PubMed: 2590185] [Full Text: https://doi.org/10.1016/0006-291x(89)91772-5]
Longo, C., Montioli, R., Bisello, G., Palazzi, L., Mastrangelo, M., Brennenstuhl, H., Polverino de Laureto, P., Opladen, T., Leuzzi, V., Bertoldi, M. Compound heterozygosis in AADC deficiency: a complex phenotype dissected through comparison among heterodimeric and homodimeric AADC proteins. Molec. Genet. Metab. 134: 147-155, 2021. [PubMed: 34479793] [Full Text: https://doi.org/10.1016/j.ymgme.2021.08.011]
Ma, J. Z., Beuten, J., Payne, T. J., Dupont, R. T., Elston, R. C., Li, M. D. Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence. Hum. Molec. Genet. 14: 1691-1698, 2005. [PubMed: 15879433] [Full Text: https://doi.org/10.1093/hmg/ddi177]
Manegold, C., Hoffmann, G. F., Degen, I., Ikonomidou, H., Knust, A., Laass, M. W., Pritsch, M., Wilichowski, E., Horster, F. Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J. Inherit. Metab. Dis. 32: 371-380, 2009. [PubMed: 19172410] [Full Text: https://doi.org/10.1007/s10545-009-1076-1]
Montioli, R., Battini, R., Paiardini, A., Tolve, M., Bertoldi, M., Carducci, C., Leuzzi, V., Voltattorni, C. B. A novel compound heterozygous genotype associated with aromatic amino acid decarboxylase deficiency: clinical aspects and biochemical studies. Molec. Genet. Metab. 127: 132-137, 2019. [PubMed: 31104889] [Full Text: https://doi.org/10.1016/j.ymgme.2019.05.004]
Montioli, R., Oppici, E., Cellini, B., Roncador, A., Dindo, M., Voltattorni, C. B. S250F variant associated with aromatic amino acid decarboxylase deficiency: molecular defects and intracellular rescue by pyridoxine. Hum. Molec. Genet. 22: 1615-1624, 2013. [PubMed: 23321058] [Full Text: https://doi.org/10.1093/hmg/ddt011]
Pons, R., Ford, B., Chiriboga, C. A., Clayton, P. T., Hinton, V., Hyland, K., Sharma, R., De Vivo, D. C. Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. Neurology 62: 1058-1065, 2004. [PubMed: 15079002] [Full Text: https://doi.org/10.1212/wnl.62.7.1058]
Scherer, L. J., McPherson, J. D., Wasmuth, J. J., Marsh, J. L. Human dopa decarboxylase: localization to human chromosome 7p11 and characterization of hepatic cDNAs. Genomics 13: 469-471, 1992. [PubMed: 1612608] [Full Text: https://doi.org/10.1016/0888-7543(92)90275-w]
Sumi-Ichinose, C., Ichinose, H., Takahashi, E., Hori, T., Nagatsu, T. Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis. Biochemistry 31: 2229-2238, 1992. [PubMed: 1540578] [Full Text: https://doi.org/10.1021/bi00123a004]