|, PKK2, ankyrin repeat and kinase domain containing 1|
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Ankyrin repeat and kinase domain containing 1 (ANKK1) also known as protein kinase PKK2 or sugen kinase 288 (SgK288) is an enzyme that in humans is encoded by the ANKK1 gene. The ANKK1 is a member of an extensive family of the Ser/Thr protein kinase family, and protein kinase superfamily involved in signal transduction pathways.
This gene contains a single nucleotide polymorphism that causes an amino acid substitution within the 11th of 12 ankyrin repeats of ANKK1 (Glu713Lys of 765 residues). This polymorphism, which is commonly referred to Taq1A, was previously believed to be located in the promoter region of the DRD2 gene, since the polymorphism is proximal to the DRD2 gene and can influence DRD2 receptor expression. It is now known to be located in the coding region of the ANKK1 gene which controls the synthesis of dopamine in the brain. The A1 allele is associated with increased activity of striatal L-amino acid decarboxylase.
- Hepatitis C infection
- Antisocial personality disorder
- Borderline personality traits
- Dissocial personality disorder
- Schizoid/avoidant behavior
Given that the A1+ allele is associated with dissocial personality disorder, one may infer that the allele is also associated with narcissistic personality disorder and histrionic personality disorder. However, these predictions have not yet been empirically verified.
A1+ genotype frequencies
European population estimates for A1+ genotype frequencies range from 20.8 to 43.4% (National Center of Biotechnology Information (NCBI), identification number rs1800497).
The ANKK1 gene is closely linked to dopamine receptor D2 (DRD2) on chromosome band 11q23.1. The A1 allele of the Taq1A polymorphism (rs1800497T), is located ≈10kb downstream of the dopamine receptor DRD2 gene. Dopamine (DA) is a neurotransmitter in the brain, which controls feeling of wellbeing. This sensation results from the interaction of dopamine and other neurotransmitters such as serotonin, the opioids, and other brain chemicals. Dopamine increases the motivation for food cravings and appetite mediation.
This single-nucleotide polymorphism (SNP) is a mutation that actually occurs in the gene encoding for the kinase ANKK1, where it causes a non-conservative amino acid substitution often called a missense mutation. This type of mutation is not always deleterious, but experts have considered it somewhat ambiguous because it can be associated to variety of diseases. The DRD2/ANKK1-Taq1A polymorphism modulates the density of the DRD2 dopamine receptors. Carriers of the A1 allele have shown up to 30% reduced receptors capacity, being the main reason why this lack of dopamine receptors predisposes individuals with this SNP mutation to seek for addictive behaviors or substances to compensate this deficiency in the dopaminergic system; such as binge eating (e.g. fat, refined carbohydrates, salt, caffeine, etc.), compulsive and impulsive behaviours (e.g. sexual activity, gambling and use of alcohol, drugs, opiates, tobacco etc.).
The Reward Deficiency Syndrome (RDS) involves the pleasures or reward mechanisms that rely on dopamine. The result of this deficiency is based on the genetic makeup; this helps explain how certain simple genetic anomalies can give rise to complex aberrant behaviours as the ones mentioned previously. The A1 allelic prevalence has been reported to be significantly higher in obese individuals that in lean subjects, moreover, individuals with increased body mass index (BMI) (BMI >30 kg/m²) have fewer DRD2 dopamine receptors. Investigators have also suggested that hormonal mechanism may underline a gender difference in the ability to suppress hunger in relation to this SNP, which may contribute to the greater incidence of obesity in women compared to men. However, authors have pointed out that A1 carriers have difficulty in learning from negative feedback in a reinforcement-learning task and are less efficient at learning to avoid actions that have negative consequences.
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- "rs1800497". Reference SNP(refSNP) Cluster Report. United States National Center for Biotechnology Information.
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