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  • Introduction The COMT gene is located on chromosomal band

    2020-01-30

    Introduction The COMT gene is located on chromosomal band 22q11.2, extends over 28 kb, contains six exons, and encodes for catechol-O-methyl-transferase (Weinshilboum and Raymond, 1977; Grossman et al., 1992; Lundström et al., 1995; Bearden et al., 2005). This enzyme plays a major role in regulation of synaptic catecholamine neurotransmitters (Badner and Gershon, 2002; Anna et al., 2017). The COMT enzyme transfers a methyl group (-CH3) onto catecholamines such as dopamine, adrenaline, epinephrine and norepinephrine, as well as onto various types of drugs or substances with a catechol structure (Lachman et al., 1996; Huang et al., 2016). The enzymes are degraded following this methylation. There are two isoforms for the COMT enzyme, the short form is soluble (S-COMT) and expressed in the peripheral tissues while the long form is bound to the cell membrane (MB-COMT) and mainly expressed by brain neurons (Nissinen and Mannisto, 2010). Both forms are normal developmental isoforms resulting from alternative transcription initiation positions. COMT is a therapeutic target since the regulation of catecholamines is impaired in several pathologies such as hypertension (Annerbrink et al., 2008; Htun et al., 2011), cardiovascular diseases (Hall et al., 2014), Asthma (Fenech and Hall, 2002) and Parkinson\'s disease (Jimenez-Jimenez et al., 2014; Lin et al., 2017; Xiao et al., 2017). One of the most common therapeutic strategies is to use a drug that targets the COMT enzymatic activity. On the other hand that enzyme activity was shown to vary as a polymorphism attributable to an amino H 89 substitution. Many variants of the COMT gene have been described as associated with the risk of various neuropsychiatric diseases such as schizophrenia (Lo Bianco et al., 2013; Lacerda-Pinheiro et al., 2014), panic disorder (Lonsdorf et al., 2010; Konishi et al., 2014; Asselmann et al., 2018), bipolar disorder (Hosang et al., 2017; Miskowiak et al., 2017; Minassian et al., 2018), anorexia nervosa (Brandys et al., 2012; Favaro et al., 2013; Peng et al., 2016). The most studied polymorphism in this gene is rs4680, a non-synonymous SNP, at codon position 108 of the soluble isoform and position 158 of the membrane bound isoform (Bertocci et al., 1991; Grossman et al., 1992; Winqvist et al., 1992; Tenhunen et al., 1994; Lundström et al., 1995; Nedic et al., 2011). The ancestral allele (G) is located in a triplet encoding amino acid Valine. The triplet with the derived allele (A) encodes the amino acid Methionine. The amino acid substitution alters the structure and causes lower enzymatic activity of COMT: the allele is associated with a 3 to 4 fold decrease in COMT activity compared to the allele (Lachman et al., 1996). Hence, individuals who have the genotype catabolize dopamine at a lower rate than individuals with the homozygous ancestral state . Heterozygous individual have an intermediate activity level as the two alleles are co-dominant. The COMT activity decrease due to the genotype promotes the accumulation of dopamine. This increase of dopamine is associated with several neuropsychological disorders (Dobryakova et al., 2015). In addition to the demonstrated importance of the 108 S-COMT/158 MB-COMT polymorphism, some studies have shown that other synonymous SNPs, that exist in this gene, may affect its expression and decrease the enzymatic activity of COMT (Nackley et al., 2006). SNP rs4818 is a synonymous variant that does not cause any change in the amino acid sequence of the enzyme. It has been shown to be associated with the activity level of COMT, the high activity allele of rs4818 being (G) (Sagud et al., 2018). This polymorphism has been shown to produce greater variation in COMT activity than rs4680 (Nackley et al., 2006). The homozygous (GG) state is associated with a high activity of the enzyme; the heterozygous genotype has an intermediate activity while the (CC) genotype has a weak enzymatic activity (Barbosa et al., 2012; Sagud et al., 2018).