Novel Arg128Ala variant in Catechol‐O‐methyltransferase gene influence persistent pain

Abstract

To the Editor: Catechol-O-methyltransferase (COMT) is ubiquitously expressed enzyme that regulates catecholamines bioavailability, playing a key role in maintaining basic physiological functions such as sympathetic tone, mood, inflammation that influence pain and also in nervous systems which mediates pain perception. There are two major forms of the COMT enzyme that differ by 50 amino acids at the N-terminus, namely membrane bound COMT and soluble COMT. The COMT gene locus is rich with single nucleotide polymorphisms (SNPs), leading to several alleles of which associated with chronic pain and pain-related phenotypes. There are some evidences of COMT gene polymorphisms, which affect COMT enzyme activity, and may adversely affects patient s ability to cope with pain. Especially COMT mutated allele G472A (Val158Met) associated with chronic post-surgical pain (CPSP) patients is reported in different ethnic population resulting in a less thermo stable enzyme with reduced activity. In this report we presenting the novel mutations p.(Arg128Ala) and the incidence of other genetic variations in exon 4 of COMT causing CPSP in sternotomy patients (Figure 1). In these patients the exon 4 of COMT gene was polymerase chain reaction amplified and sequenced, sequence analysis revealed the presence of different variations of COMT alleles in 25% (25/100) of CPSP patients having numeric rating scale (NRS) >4 pain score. Twenty of these patients had already reported Val158Met COMT allele, while, in 5% of patients showed novel mutations c.382C>G, c.383G>C; p. (Arg128Ala). There are six SNPs reported so far with high polymorphism frequency rs2097903, rs6269, rs4633, rs165599, rs4818 and rs4680. The SNP rs4680 is non-synonymous and codes for a substitution of valine (Val) to methionine (Met) at codon 158 (Val158Met). Hence we evaluated the influence of COMT exon 4 mutations in post-operative cardiac patients. Corroborating to our study out of 100 patients 25 patients had “pain complaint” in which 20 patients have Val158Met (G472A). In contrast to this five patients with “pain complaint” have not shown Val158Met (G472A). However set of Novel mutations have been observed in these five patients assumed to be the cause of pain (GenBank accession numbers: MK509812, MK509813, MK509814, MK509815 and MK509816). To our prospect out of five patients with “pain complaint” without Val158Met (G472A) variation, all of them, that is, 100% had c.382C>G, c.383G>C mutations resulted in p.(Arg128Ala) were observed. 60% (3/5 patients) were having c.373C>G and c.408C>G resulted in p.(Arg125Gly) and p. (Leu136Leu) Silent mutation. 40% (2/5 patients) were having c.372G>C; p.(Val124Val) and 20% (among in any 1/5 patients) have c.349G>A, c.351C>A, c.359G>C, c.370G>A, c.379G>C resulted in p. (Ala117Thr), p.(Ala117Ala) Silent mutation, p.(Gly120Ala), p. (Val124Met), p.(Ala127Pro). These results indicated genetic variations having novel and silent mutations of COMT gene associated with CPSP. Interestingly the patient 39 and 72 had similar mutations hence the results for both the patients were found to be same. Further we noticed that all these patients have silent mutations in which the change in nucleotide sequence does not alter amino acid codes, this condition may persuade in developing missense/nonsense mutations in future generations. This is the first study wherein we observed the impact of the COMT exon 4 novel mutations in patients showing CPSP even after 3 months with NRS scores ≥4.