No excess of loss-of-function of COQ2 variants in pathologically confirmed multiple system atrophy (S15.005)

BACKGROUND: Multiple system atrophy (MSA) is a fatal late onset neurodegenerative disease of unknown etiology. Tsuji and colleagues recently reported an association between COQ2 variants in Japanese patients and familial and sporadic clinically diagnosed MSA. Their study was based on linkage analysis and genome sequencing in families through which homozygous and compound heterozygous COQ2 mutations were detected in two families. Decreased growth rates in COQ2 mutants identified in MSA were detected in a yeast complementation assay, a finding consistent with the view that the association with disease was caused by loss-of-function in the protein encoded by COQ2. They also performed an association between rare variants in COQ2 and risk of MSA in clinical MSA cases and propose that the variant V393A (referred to by Tsuji and colleagues as V343A) increases the risk of developing MSA. METHODS: In a multicentre collaboration, we sequenced coding regions and flanking introns of COQ2 (ENS0311469, CCDS47090.2, NM_015697.7) in more than 300 patients with neuropathologically confirmed MSA and 262 controls, all of European descent. RESULTS: We identified a COQ2 nonsense variant that was more common in controls than in persons with MSA (R22X, 24 vs. 9 alleles; P<0.002) and two other variants (rs6818847, p.V66L; and rs6535454, p.D298D), which were also more common in controls. We failed to detect the variant V393A (referred to by Tsuji and colleagues as V343A) that was reported to be associated with MSA in Japanese patients. CONCLUSION: Our data do not support an association between loss-of-function COQ2 variants and increased risk of pathologically confirmed MSA in Europeans. Study supported by: The authors are grateful to the MRC UK, The Wellcome Trust, the MSA Trust and the NIHR UCLH BRC for funding this work. Disclosure: Dr. Schottlaender has nothing to disclose. Dr. Houlden has nothing to disclose.