COQ2 – Multiple System Atrophy

Genetic studies in Japanese multiplex families identified homozygous (M78V-V343A/M78V-V343A) and compound heterozygous (R337X/V343A) COQ2 mutations segregating with MSA in two pedigrees (PMID:23758206). Subsequent East Asian case–control series and a meta-analysis encompassing Japanese, Korean, mainland Chinese, and Taiwanese cohorts demonstrated a significant association of the heterozygous c.1178T>C (p.Val393Ala) susceptibility variant with the cerebellar subtype of MSA (MSA-C; pooled OR 2.12, p = 0.004) (PMID:26590992; PMID:34455210). However, large cohorts from Italy and the United States failed to replicate these findings in Caucasian populations (PMID:31398377; PMID:25373618), and a cosegregation analysis of the c.-23C>G variant did not support pathogenicity (PMID:27394078). Overall, an autosomal recessive inheritance model with incomplete penetrance is proposed but remains unconfirmed.

Functional assays confirm that COQ2 missense and loss-of-function variants impair para-hydroxybenzoate-polyprenyltransferase activity, leading to deficient coenzyme Q10 biosynthesis in patient fibroblasts and yeast complementation models (PMID:16400613; PMID:17374725). CoQ10 levels are significantly reduced in the cerebellum of MSA patients and in plasma of MSA cohorts, supporting a pathogenic mechanism driven by mitochondrial dysfunction and oxidative stress independent of COQ2 genotype (PMID:27235405; PMID:27356913). Despite strong mechanistic plausibility, inconsistent replication across populations and limited segregation data yield a Limited classification. COQ2 genotyping in MSA-C patients may inform risk stratification and highlight potential benefit from CoQ10 supplementation.

References

• The New England Journal of Medicine • 2013 • Mutations in COQ2 in familial and sporadic multiple-system atrophy PMID:23758206
• Neurological Sciences • 2016 • Association of the COQ2 V393A variant with risk of multiple system atrophy in East Asians: a case-control study and meta-analysis of the literature PMID:26590992
• Journal of the Neurological Sciences • 2021 • COQ2 V393A confers high risk susceptibility for multiple system atrophy in East Asian population PMID:34455210
• Gene • 2019 • Genetic mutation analysis of the COQ2 gene in Italian patients with multiple system atrophy PMID:31398377
• Molecular Neurodegeneration • 2014 • Analysis of COQ2 gene in multiple system atrophy PMID:25373618
• Neurobiology of Aging • 2016 • Mutational analysis of COQ2 in patients with MSA in Italy PMID:27394078
• American Journal of Human Genetics • 2006 • A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency PMID:16400613
• Human Molecular Genetics • 2007 • Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis PMID:17374725
• Journal of Neuropathology & Experimental Neurology • 2016 • Decreased Coenzyme Q10 Levels in Multiple System Atrophy Cerebellum PMID:27235405
• JAMA Neurology • 2016 • Plasma Coenzyme Q10 Levels in Patients With Multiple System Atrophy PMID:27356913

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