Identification of a common polymorphism in COQ8B acting as a modifier of thoracic aortic aneurysm severity

Landis, Benjamin J.; Lai, Dongbing; Guo, Dongchuan; Corvera, Joel S.; Idrees, Muhammad T.; Stadler, Henry; Cuevas, Christian; Needler, Gavin U.; Vujakovich, Courtney E.; Milewicz, Dianna M.; Hinton, Robert B.; Ware, Stephanie M.

doi:10.1016/j.xhgg.2021.100057

Cited by 4 publications

(4 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, excessive generation of ROS may be the responsible mechanism. COQ8B , important for the biosynthesis of Coenzyme Q, has been identified as a candidate genetic modifier of TAA severity (Landis et al, 2022). COQ8B localizes to mitochondria in SMCs, and loss of mitochondrial COQ8B leads to increased ROS, decreased mitochondrial respiration, and altered expression of SMC contractile genes (Landis et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Novel phenotype of aortic root dilatation and late‐onset metabolic decompensation in a patient with TMEM70 deficiency

Mackay

Gijavanekar

Streff

et al. 2023

American J of Med Genetics Pt A

View full text Add to dashboard Cite

TMEM70 deficiency causing mitochondrial complex V deficiency, nuclear type 2 (MIM: 614052) is the most common nuclear encoded defect affecting ATP synthase and has been well described in the literature as being characterized by neonatal or infantile onset of poor feeding, hypotonia, lethargy, respiratory compromise, heart failure, lactic acidosis, hyperammonemia, and 3‐methylglutaconic aciduria progressing to a phenotype of developmental delay, failure to thrive, short stature, nonprogressive cardiomyopathy, microcephaly, facial dysmorphisms, hypospadias, persistent pulmonary hypertension of the newborn, and Wolff–Parkinson–White syndrome, as well as metabolic crises followed by developmental regression. The patient with TMEM70 deficiency herein reported has the unique presentation of aortic root dilatation, differing facial dysmorphisms, and no history of neonatal metabolic decompensation or developmental delay, as well as a plasma metabolomics signature, including elevated 3‐methylglutaconic acid, 3‐methylglutarylcarnitine, alanine, and lactate, in addition to the commonly described increased 3‐methylglutaconic acid on urine organic acid analysis that helped aid in the diagnostic interpretation of variants of uncertain significance in TMEM70.

show abstract

Section: Discussionmentioning

confidence: 99%

Novel phenotype of aortic root dilatation and late‐onset metabolic decompensation in a patient with TMEM70 deficiency

Mackay

Gijavanekar

Streff

et al. 2023

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…In the context of GWAS, various SNPs have been discovered to be associated with either a decreased or elevated risk of ATAA progression. In addition, several novel genes, including CD40 [ 36 ], ESR1 [ 233 ], COQB1 [ 109 ], ENTPD1, PDLIM5 (PDZ and LIM domain 5), ACTN4 (alpha-actinin-4) , and GLRX [ 33 ] have been identified in the context of ATAA.…”

Section: Identified Genes In Familial Ataamentioning

confidence: 99%

“…The mechanistic involvement of COQB1 in the association with ATAA is explained by the negative feedback of rs386542, which elevates COQB1 expression. This increase in COQB1 expression leads to heightened VSMC metabolic activity, ultimately resulting in a decreased risk of ATAA [ 109 ].…”

Section: Identified Genes In Familial Ataamentioning

confidence: 99%

Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections

Ganizada,

Veltrop,

Akbulut

et al. 2024

Basic Res Cardiol

View full text Add to dashboard Cite

Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM–VSMC network.

show abstract

“…The following supporting information can be downloaded at: , Table S1: Comprehensive list of analyzed variants. References [ 71 , 72 , 74 , 90 , 91 , 92 , 93 , 96 , 99 , 100 , 103 , 111 , 115 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ] were cited in supplementary.…”

mentioning

confidence: 99%

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

Wang¹,

Jain²,

Novales³

et al. 2022

Antioxidants

View full text Add to dashboard Cite

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.

show abstract

Identification of a common polymorphism in COQ8B acting as a modifier of thoracic aortic aneurysm severity

Cited by 4 publications

References 34 publications

Novel phenotype of aortic root dilatation and late‐onset metabolic decompensation in a patient with TMEM70 deficiency

Novel phenotype of aortic root dilatation and late‐onset metabolic decompensation in a patient with TMEM70 deficiency

Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections

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

Contact Info

Product

Resources

About