Predicting and Understanding the Pathology of Single Nucleotide Variants in Human COQ Genes

Abstract

Coenzyme Q (CoQ) is a vital lipid that functions as an electron carrier in the mitochondrial electron transport chain and as a membrane-soluble antioxidant. Deficiencies in CoQ lead to metabolic diseases with a wide range of clinical manifestations. There are currently few treatments that can slow or stop disease progression. Primary CoQ10 deficiency can arise from mutations in any of the COQ genes responsible for CoQ biosynthesis. While many mutations in these genes have been identified, the clinical significance of most of them remains unclear. Here we analyzed the structural and functional impact of 429 human missense single nucleotide variants (SNVs) that give rise to amino acid substitutions in the conserved and functional regions of human genes encoding a high molecular weight complex known as the CoQ synthome (or Complex Q), consisting of the COQ3–COQ7 and COQ9 gene products. Using structures of COQ polypeptides, close homologs, and AlphaFold models, we identified 115 SNVs that are potentially pathogenic. Further biochemical characterizations in model organisms such as Saccharomyces cerevisiae are required to validate the pathogenicity of the identified SNVs. Collectively, our results will provide a resource for clinicians during patient diagnosis and guide therapeutic efforts toward combating primary CoQ10 deficiency.

Predicting the effects of rare genetic variants on oncogenic signaling pathways: A computational analysis of HRAS protein function

“…Similarly, the G115R mutation, also predicted to be deleterious, can lead to an incorrect conformation and disturbance of the local structure of the protein due to the larger size of the mutant residue, as a result, compare with (Wang S et al, 2022), and this result in loss of protein function. The G13R mutation located in the G-domain in the G-domain can cause loss of interaction because the mutant residue is more minor and has a different hydrophobicity compared to the wild-type residue as per earlier researchers (O'Bryan, 2019).…”

AlphaFold Structure Analysis of COQ2 as Key Component of the Coenzyme Q Synthesis Complex

“…CoQ is of paramount importance because of its universal role in the respiratory chain as an electron carrier. However, additional functions have been proposed [1][2][3][4]. In bacteria, it has been associated with other processes such as response to oxidative stress, formation of disulphide bonds and regulation of gene expression [5,6], whereas in eukaryotes a plethora of both mitochondrial and extramitochondrial functions have been identified.…”

“…The proteins involved in CoQ biosynthesis are generally known as Ubi proteins in prokaryotes and COQ proteins in eukaryotes [1,3,15]. Thirteen proteins encoded in the nucleus genome take part in this pathway in humans: COQ2, COQ3, COQ4, COQ5, COQ6, COQ7, COQ8A (ADCK3), COQ8B (ADCK4), COQ9, COQ10A, COQ10B, PDSS1 (DPS1) and PDSS2 (DLP1) [4]. Mutations in some of these proteins (COQ2, COQ4, COQ6, COQ7, COQ8A, COQ8B, PDSS1 and PDSS2) have been related to primary CoQ deficiency in humans that encompasses rare autosomal recessive diseases characterized by a wide heterogeneity of symptoms, severity and age of onset, mainly affecting organs with high energy needs, such as brain, inner ear, muscles, heart and kidneys [1,3].…”

An AlphaFold Structure Analysis of COQ2 as Key a Component of the Coenzyme Q Synthesis Complex

“…CoQ is of paramount importance because of its universal role in the respiratory chain as an electron carrier. However, additional functions have been proposed [1][2][3][4]. In bacteria, it has been associated with other processes such as the response to oxidative stress, formation of disulfide bonds and regulation of gene expression [5,6], whereas in eukaryotes, a plethora of both mitochondrial and extramitochondrial functions have been identified.…”

“…The proteins involved in CoQ biosynthesis are generally known as Ubi proteins in prokaryotes and COQ proteins in eukaryotes [1,3,15]. Thirteen proteins encoded in the nucleus genome take part in this pathway in humans: COQ2, COQ3, COQ4, COQ5, COQ6, COQ7, COQ8A (ADCK3), COQ8B (ADCK4), COQ9, COQ10A, COQ10B, PDSS1 (DPS1) and PDSS2 (DLP1) [4]. Mutations in some of these proteins (COQ2, COQ4, COQ6, COQ7, COQ8A, COQ8B, PDSS1 and PDSS2) have been related to primary CoQ deficiency in humans, which encompasses rare autosomal recessive diseases characterized by a wide heterogeneity of symptoms, severity and age of onset, mainly affecting organs with high energy needs, such as the brain, inner ear, muscles, heart and kidneys [1,3].…”