Abstract
BackgroundLoss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). It has also been proposed that specific heterozygous variants in the COQ2 gene may confer susceptibility to sporadic MSA. To assess the frequency of COQ2 variants in patients with MSA, we sequenced the entire coding region and investigated all exonic copy number variants of the COQ2 gene in 97 pathologically-confirmed and 58 clinically-diagnosed MSA patients from the United States.ResultsWe did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients. In two patients, we identified two heterozygous COQ2 variants (p.S54W and c.403 + 10G > T) of unknown significance, which were not observed in 360 control subjects. We also identified one heterozygous carrier of a known loss of function p.S146N substitution in a severe MSA-C pathologically-confirmed patient.ConclusionsThe COQ2 p.S146N substitution has been previously reported as a pathogenic mutation in primary CoQ10 deficiency (including infantile multisystem disorder) in a recessive manner. This variant is the third primary CoQ10 deficiency mutation observed in an MSA case (p.R387X and p.R197H). Therefore it is possible that in the heterozygous state it may increase susceptibility to MSA. Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-44) contains supplementary material, which is available to authorized users.
Highlights
Loss of function coenzyme Q2 4hydroxybenzoate polyprenyltransferase gene (COQ2) mutations results in primary coenzyme Q10 (CoQ10) deficiency
A homozygous mutation p.M128V-V393A/ p.M128V-V393A and compound heterozygous mutations p.R387X/p.V393A in the coenzyme Q2 4hydroxybenzoate polyprenyltransferase gene (COQ2; OMIM 609825) were identified in affected members of two unrelated Japanese families with multiple system atrophy (MSA) [4]. This is the first report of recessive COQ2 pathogenic mutations in adults, recessive COQ2 mutations are known to cause primary coenzyme Q10 (CoQ10) deficiency-1 (COQ10D1; OMIM 607426) which includes phenotype of infantile multisystem disorder or nephrotic syndrome [5,6,7,8,9,10,11,12]; COQ2 is involved in the synthesis of CoQ10
We found one homozygous and five heterozygous carriers of p.R22X in 155 MSA patients, but there was no significant difference between patients and control subjects or patients and Exome Variant Server (EVS) data or 1000 Genomes data (Table 1; Additional file 1)
Summary
Loss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). There are no Recently, a homozygous mutation p.M128V-V393A/ p.M128V-V393A (referred to by Tsuji and colleagues as p.M78V-V343A/p.M78V-V343A) and compound heterozygous mutations p.R387X/p.V393A (referred to by Tsuji and colleagues p.R337X/p.V343A) in the coenzyme Q2 4hydroxybenzoate polyprenyltransferase gene (COQ2; OMIM 609825) were identified in affected members of two unrelated Japanese families with MSA [4] This is the first report of recessive COQ2 pathogenic mutations in adults, recessive COQ2 mutations are known to cause primary coenzyme Q10 (CoQ10) deficiency-1 (COQ10D1; OMIM 607426) which includes phenotype of infantile multisystem disorder or nephrotic syndrome [5,6,7,8,9,10,11,12]; COQ2 is involved in the synthesis of CoQ10. Given the proposed loss-offunction mechanism we investigated exon dosage as a possible disease-related phenomenon
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