The identification of genetic variation in the acyl-CoA synthetase genes (ACSM2A and ACSM2B)
Van der Westhuizen, Taryn
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Investigations into the role of the glycine conjugation pathway and specifically the functioning and significant importance of the mitochondrial medium-chain ligases have seriously been neglected over the last 30 years. The metabolism of drugs and benzoate to acyl coenzyme A (CoA) intermediates in humans has increased in recent times as the exposure to environmental factors, nutrition and the chronic use of medication rises. Seeing that no defect of the glycine conjugation pathway has been reported thus far, it can be assumed that this pathway is essential for survival. In this study the question was raised on whether the human acyl CoA synthetase medium-chain family member 2B (ACSM2B) open reading frame (ORF) is also as highly conserved as previously reported for the Glycine N-acyltransferase (GLYAT) ORF. It was hypothesised that genetic variation in the ORF of the ACSM2B gene should be low. However, focus was also on the human acyl CoA synthetase medium-chain family member 2A (ACSM2A) gene as there is some confusion in current literature regarding the distinction of these two highly similar genes. The hypothesis was investigated by analysing the genetic variation data across 6 different population groups (AFR; EUR; EAS; AMR; AA; EA) of the ACSM2A and ACSM2B ORF available on public databases, along with the coding region of a small cohort of South African Afrikaner Caucasian individuals that was sequenced. The ACSM2A and ACSM2B ORF of 8537 individuals (consisting of data aquired from the 1000 Genomes Project, NHLBI ESP and South African Afrikaner Caucasian) analysed, identified genetic variants at a low frequency (%) and mostly occurring only as heterozygotes and in a single population group. Of the 47 (1000 Genomes Project), 15 (National Heart, Lung and Blood Institute Exome Sequencing Project, NHLBI ESP), and 4 (South African Afrikaner Caucasian Population, SA) non-synonymous SNPs identified within the coding region of the ACSM2A gene, the L64P variant had the highest homozygous SNP genotype frequency (29.0%), followed by the N463D (12.5%), and the R5Q variant (5.5%). All other variants were found at frequencies <5%. Of the 43 (1000 Genomes Project), 15 (National Heart, Lung and Blood Institute Exome Sequencing Project, NHLBI ESP), and 1 (South African Afrikaner Caucasian Population, SA) non-synonymous SNPs identified within the coding region of the ACSM2B gene, the T278A variant had the highest homozygous SNP genotype frequency (4.0%), followed by the I305V variant (0.7%), and the D322N variant (0.1%). The results of this study indicated that the acyl CoA synthetase gene ACSM2B ORF is not as highly conserved as the GLYAT ORF, as ACSM2B is not part of the evolutionary path of polyphenol biotransformation. However, it is evident from this study that very low genotype frequencies exist for the SNPs identified within the coding region of the ACSM2B gene (T278A: 4.0%, I305V: 0.7%, D322N: 0.1%) compared to genotype frequencies identified for GLYAT (N156S: 90%; S17T: 4.6%; R131H: 0.1%) from a study conducted by Van der Sluis et al., (2015). The results of this study indicated that the acyl CoA synthetase genes (ACSM2A and ACSM2B) ORF is relatively conserved and that the current reference sequence used in the present study for the ACSM2A and ACSM2B genes should probably be considered as the wild-type. With increased levels of benzoic acid exposure in humans, the HXM-A protein (encoded by ACSM2B) might not be able to effectively detoxify such large amounts. Thus, findings underline the importance of future investigations into the ACSM2A and ACSM2B genes, and their proteins to better understand the effect of SNPs on protein function. This study also contributed significantly to a better understanding of the nomenclature regarding the acyl CoA synthetase genes, especially confusion surrounding the ACSM2A and ACSM2B genes as several discrepancies in the literature were pointed out.