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DDC
dopa decarboxylase
The DDC gene encodes the aromatic L-amino acid decarboxylase (AADC) enzyme, which is vital for synthesising neurotransmitters like dopamine and serotonin in the brain and nervous system. The DDC gene is responsible for producing the AADC enzyme, a key component in the biochemical pathways that create dopamine and serotonin.
DDC is located on the short (p) arm of chromosome 7, at band 7p12.2-p12.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The DDC gene provides the genetic blueprint for the aromatic L-amino acid decarboxylase (AADC) enzyme, a critical protein in the human body. This enzyme plays a fundamental role in the brain and wider nervous system by facilitating the production of important neurotransmitters. Neurotransmitters are chemical signals that allow nerve cells (neurons) to communicate with each other and with other cell types, influencing numerous bodily functions.
Disruptions in the DDC gene's function can lead to reduced AADC enzyme activity, which in turn affects neurotransmitter levels and can result in significant neurological health issues.
What the gene does
The AADC enzyme, produced from the DDC gene, is instrumental in the final stages of dopamine and serotonin synthesis. It acts as a decarboxylase, removing a carboxyl group from specific precursor molecules.
In dopamine production, the AADC enzyme converts L-dopa, a molecule derived from the amino acid tyrosine, directly into dopamine. Dopamine itself is a precursor for other neurotransmitters, including norepinephrine and epinephrine. Similarly, in the synthesis of serotonin, the AADC enzyme transforms 5-hydroxytryptophan, which originates from the amino acid tryptophan, into serotonin. Both dopamine and serotonin are crucial for regulating mood, movement, cognition, and other essential neurological processes. Impaired activity of the AADC enzyme, due to DDC gene variants, disrupts these vital pathways.
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Chromosome location
The DDC gene is situated on the short arm of chromosome 7, specifically within the 7p12.2-p12.1 region. This chromosomal location indicates its precise position within the human genome. The DDC gene consists of multiple exons and introns, which are typical structural components of protein-coding genes.
Protein structure
The AADC protein, encoded by the DDC gene, has a length of 480 amino acids. Its structure includes several distinct regions. There is a specific domain referred to as '1 (Repeat)' spanning amino acids 58-115. Additionally, the protein contains '2 X approximate tandem repeats (Region)' located between amino acids 58-178, which encompasses the '2 (Repeat)' region from amino acids 118-178. These structural elements contribute to the enzyme's overall shape and catalytic activity.
Key variants
Variants in the DDC gene can alter the normal function of the aromatic L-amino acid decarboxylase (AADC) enzyme. These genetic changes can lead to a reduction in the enzyme's activity, affecting its ability to produce essential neurotransmitters. Different types of variants, including missense, nonsense, and frameshift changes, have been identified.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1041+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of aromatic-L-amino-acid decarboxylase |
c.1055del | p.Pro352fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of aromatic-L-amino-acid decarboxylase |
c.1123C>T | p.Gln375Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of aromatic-L-amino-acid decarboxylase |
c.1241dup | p.Ser416fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.128del | p.Pro43fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of aromatic-L-amino-acid decarboxylase |
c.1339C>T | p.Arg447Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of aromatic-L-amino-acid decarboxylase |
c.1340G>A | p.Arg447His | Pathogenic | ★★☆☆ | Deficiency of aromatic-L-amino-acid decarboxylase |
c.140C>A | p.Pro47His | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of aromatic-L-amino-acid decarboxylase |
c.175G>A | p.Asp59Asn | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of aromatic-L-amino-acid decarboxylase |
c.201+5G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of aromatic-L-amino-acid decarboxylase |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants within the DDC gene are the underlying cause of Aromatic L-amino acid decarboxylase deficiency. This inherited disorder impacts how neurons transmit information, often leading to neurological problems early in life. The reduced activity of the AADC enzyme due to DDC gene variants results in lower than normal levels of dopamine and serotonin, which are critical for proper brain function.
Inheritance pattern
Conditions caused by pathogenic DDC variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The DDC gene is featured on several UK NHS National Genomic Test Directory panels, indicating its clinical relevance in the UK. It holds a 'green' status on the DDG2P panel, as well as panels for Dystonia, chorea or related movement disorder (childhood onset, R57), Early onset dystonia, Early onset or syndromic epilepsy, Intellectual disability, Likely inborn error of metabolism (R98), Neurotransmitter disorders, and Undiagnosed metabolic disorders. This green status signifies that variants in DDC are considered diagnostically significant for these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the DDC gene?
The DDC gene provides instructions for making the aromatic L-amino acid decarboxylase (AADC) enzyme, which is crucial for the final steps in producing neurotransmitters like dopamine and serotonin.
What health condition is associated with DDC gene variants?
Variants in the DDC gene cause Aromatic L-amino acid decarboxylase deficiency, an inherited disorder that affects neurotransmitter production and can lead to neurological problems.
How does the AADC enzyme make dopamine?
The AADC enzyme converts L-dopa, a precursor molecule, into dopamine by removing a carboxyl group during the final step of the dopamine synthesis pathway.
References
- Brun L, Ngu LH, Keng WT. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010. PMID: 20505134
- Verbeek MM, Geurtz PB, Willemsen MA. Aromatic L-amino acid decarboxylase enzyme activity in deficient patients and heterozygotes. Molecular genetics and metabolism. 2007. PMID: 17240182
- Hyland K. Inherited disorders affecting dopamine and serotonin: critical neurotransmitters derived from aromatic amino acids. The Journal of nutrition. 2007. PMID: 17513427
- Pearl PL, Taylor JL, Trzcinski S. The pediatric neurotransmitter disorders. Journal of child neurology. 2007. PMID: 17690069
- Yu Y, Panhuysen C, Kranzler HR. Intronic variants in the dopa decarboxylase (DDC) gene are associated with smoking behavior in European-Americans and African-Americans. Human molecular genetics. 2006. PMID: 16740595
- Zhang H, Ye Y, Wang X. DOPA decarboxylase gene is associated with nicotine dependence. Pharmacogenomics. 2006. PMID: 17184203
- Pearl PL, Capp PK, Novotny EJ. Inherited disorders of neurotransmitters in children and adults. Clinical biochemistry. 2005. PMID: 16298354