Implication of a rare variant in OPA1 in Cardiac Pathophysiology: From Cristae Remodelling to Contractile Dysfunction
gupta, m.; Mukhopadhyay, A.; Kumar, A.; Mohapatra, B. · genetics · 2026-09-04 · 原文
DOI：10.64898/2026.08.31.748193作者：4 位
Abstract Optic Atrophy 1 (OPA1), an important inner mitochondrial membrane GTPase, regulates mitochondrial fusion, maintains cristae structure, calcium buffering, cellular bioenergetics, preserves mtDNA and controls apoptosis. Here we examined the role of OPA1 variants in DCM using whole-exome sequencing (WES) of 5 familial and 10 sporadic DCM cases. A rare de novo OPA1 variant, c.563C>T (p.Pro188Leu), was identified in a DCM patient, which is absent in 100 healthy controls as well as in the 1000 Genomes, IndiGenomes and GenomeAsia 100k databases while it showed very low MAF (0.000069) in GnomAD. Structural modelling predicted the variant to be highly deleterious and revealed marked conformational distortion of the mutant protein (RMSD = 3.5 Angstrom). Molecular docking further demonstrated enhanced accessibility of mutant OPA1 to mitochondrial protease OMA1, suggesting increased OPA1 proteolytic processing and a consequent increase in mitochondrial fragmentation. Functional analysis in stable H9C2 cardiomyoblast cells, demonstrated significantly reduced OPA1 protein expression, extensive mitochondrial fragmentation in mutant-OPA1 expressing cells. The mutant protein caused signifi
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1. 人话版
Abstract Optic Atrophy 1 (OPA1), an important inner mitochondrial membrane GTPase, regulates mitochondrial fusion, maintains cristae structure, calcium buffering, cellular bioenergetics, preserves mtDNA and controls apoptosis.
Here we examined the role of OPA1 variants in DCM using whole-exome sequencing (WES) of 5 familial and 10 sporadic DCM cases.
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4. 证据与数字
A rare de novo OPA1 variant, c.563C>T (p.Pro188Leu), was identified in a DCM patient, which is absent in 100 healthy controls as well as in the 1000 Genomes, IndiGenomes and GenomeAsia 100k databases while it showed very low MAF (0.000069) in GnomAD.
Structural modelling predicted the variant to be highly deleterious and revealed marked conformational distortion of the mutant protein (RMSD = 3.5 Angstrom).
Molecular docking further demonstrated enhanced accessibility of mutant OPA1 to mitochondrial protease OMA1, suggesting increased OPA1 proteolytic processing and a consequent increase in mitochondrial fragmentation.
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