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Analysis of COQ2 gene in multiple system atrophy.

Ogaki K, Fujioka S, Heckman MG, Rayaprolu S, Soto-Ortolaza AI, Labbé C, Walton RL, Lorenzo-Betancor O, Wang X, Asmann Y, Rademakers R, Graff-Radford N, Uitti R, Cheshire WP, Wszolek ZK, Dickson DW, Ross OA - Mol Neurodegener (2014)

Bottom Line: Loss of function COQ2 mutations results in primary CoQ10 deficiency.We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ross.owen@mayo.edu.

ABSTRACT

Background: 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). 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.

Results: We 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.

Conclusions: The 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.

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Related in: MedlinePlus

COQ2variants and transcripts. The upper three panels in blue represents the protein coding transcripts of the COQ2 gene and the exons are numbered (transcripts which cause nonsense mediated decay or transcripts which produce no protein are not shown). Transcripts and protein domains are referred to Ensemble (http://useast.ensembl.org/index.html) and 1000 Genomes (http://www.1000genomes.org/home). The lower three panels represent the protein domains and motifs by Forsgren and colleagues [14], TIGRFAMs database (http://www.tigr.org/TIGRFAMs) [15] and Pfam database (http://pfam.xfam.org/) [16]. There were no transcripts which start from second ATG. Red box indicates the allylic polyprenyl diphosphate substrate-binding site. Purple Boxes indicate the six transmembrane domains (TMD) predicted. The orange box and green box show the areas of 4-hydroxybenzoate polyprenyl transferase (Accession: TIGR01474) and UbiA prenyltransferase family (Accession: PF01040) respectively. Potential risk variants and p.R22X shown in black were identified in multiple system atrophy (MSA) [4, 13, 17]. p.R22X only exists on the longest isoform, COQ2-001, and does not associated with MSA. †ENST00000439031 was missing in the latest Ensembl release 77 - October 2014. *Asterisks indicate variants found in our MSA series. Arrow shows an intronic variant, c403 + 10G > T (Exon1 + 10). Mutations in blue were identified in primary coenzyme Q10 (CoQ10) deficiency [5–12]. Mutations in red (p.S146N, p.R197H and p.R387X) were identified both in MSA and primary CoQ10 deficiency [4, 6, 8, 13].
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Fig1: COQ2variants and transcripts. The upper three panels in blue represents the protein coding transcripts of the COQ2 gene and the exons are numbered (transcripts which cause nonsense mediated decay or transcripts which produce no protein are not shown). Transcripts and protein domains are referred to Ensemble (http://useast.ensembl.org/index.html) and 1000 Genomes (http://www.1000genomes.org/home). The lower three panels represent the protein domains and motifs by Forsgren and colleagues [14], TIGRFAMs database (http://www.tigr.org/TIGRFAMs) [15] and Pfam database (http://pfam.xfam.org/) [16]. There were no transcripts which start from second ATG. Red box indicates the allylic polyprenyl diphosphate substrate-binding site. Purple Boxes indicate the six transmembrane domains (TMD) predicted. The orange box and green box show the areas of 4-hydroxybenzoate polyprenyl transferase (Accession: TIGR01474) and UbiA prenyltransferase family (Accession: PF01040) respectively. Potential risk variants and p.R22X shown in black were identified in multiple system atrophy (MSA) [4, 13, 17]. p.R22X only exists on the longest isoform, COQ2-001, and does not associated with MSA. †ENST00000439031 was missing in the latest Ensembl release 77 - October 2014. *Asterisks indicate variants found in our MSA series. Arrow shows an intronic variant, c403 + 10G > T (Exon1 + 10). Mutations in blue were identified in primary coenzyme Q10 (CoQ10) deficiency [5–12]. Mutations in red (p.S146N, p.R197H and p.R387X) were identified both in MSA and primary CoQ10 deficiency [4, 6, 8, 13].

Mentions: In this study, our sequence analysis of COQ2 in 155 MSA patients identified eleven variants including one intronic, six synonymous, three non-synonymous and one nonsense variants (Table 1), however exon dosage assays did not detect any deletion/multiplication. Four variants are common, p.R22X, p.L66V, p.D298D and p.S330S, and present in the Exome Variant Server (EVS) and 1000 Genomes; there was no significant minor allele frequency (MAF) difference with our patients, EVS data, or 1000 Genomes data (Table 1; Additional file 1). 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 EVS data or 1000 Genomes data (Table 1; Additional file 1). This variant is incorporated into one of the longer COQ2 transcripts (Figure 1); given the frequency of this variant and the presence of homozygotes both in our study and the EVS, it is unlikely this variant is of clinical relevance in primary CoQ10 deficiency or MSA. Indeed, Schottlaender and Houlden recently reported that p.R22X was more common in controls than cases [13].Table 1


Analysis of COQ2 gene in multiple system atrophy.

Ogaki K, Fujioka S, Heckman MG, Rayaprolu S, Soto-Ortolaza AI, Labbé C, Walton RL, Lorenzo-Betancor O, Wang X, Asmann Y, Rademakers R, Graff-Radford N, Uitti R, Cheshire WP, Wszolek ZK, Dickson DW, Ross OA - Mol Neurodegener (2014)

COQ2variants and transcripts. The upper three panels in blue represents the protein coding transcripts of the COQ2 gene and the exons are numbered (transcripts which cause nonsense mediated decay or transcripts which produce no protein are not shown). Transcripts and protein domains are referred to Ensemble (http://useast.ensembl.org/index.html) and 1000 Genomes (http://www.1000genomes.org/home). The lower three panels represent the protein domains and motifs by Forsgren and colleagues [14], TIGRFAMs database (http://www.tigr.org/TIGRFAMs) [15] and Pfam database (http://pfam.xfam.org/) [16]. There were no transcripts which start from second ATG. Red box indicates the allylic polyprenyl diphosphate substrate-binding site. Purple Boxes indicate the six transmembrane domains (TMD) predicted. The orange box and green box show the areas of 4-hydroxybenzoate polyprenyl transferase (Accession: TIGR01474) and UbiA prenyltransferase family (Accession: PF01040) respectively. Potential risk variants and p.R22X shown in black were identified in multiple system atrophy (MSA) [4, 13, 17]. p.R22X only exists on the longest isoform, COQ2-001, and does not associated with MSA. †ENST00000439031 was missing in the latest Ensembl release 77 - October 2014. *Asterisks indicate variants found in our MSA series. Arrow shows an intronic variant, c403 + 10G > T (Exon1 + 10). Mutations in blue were identified in primary coenzyme Q10 (CoQ10) deficiency [5–12]. Mutations in red (p.S146N, p.R197H and p.R387X) were identified both in MSA and primary CoQ10 deficiency [4, 6, 8, 13].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4233093&req=5

Fig1: COQ2variants and transcripts. The upper three panels in blue represents the protein coding transcripts of the COQ2 gene and the exons are numbered (transcripts which cause nonsense mediated decay or transcripts which produce no protein are not shown). Transcripts and protein domains are referred to Ensemble (http://useast.ensembl.org/index.html) and 1000 Genomes (http://www.1000genomes.org/home). The lower three panels represent the protein domains and motifs by Forsgren and colleagues [14], TIGRFAMs database (http://www.tigr.org/TIGRFAMs) [15] and Pfam database (http://pfam.xfam.org/) [16]. There were no transcripts which start from second ATG. Red box indicates the allylic polyprenyl diphosphate substrate-binding site. Purple Boxes indicate the six transmembrane domains (TMD) predicted. The orange box and green box show the areas of 4-hydroxybenzoate polyprenyl transferase (Accession: TIGR01474) and UbiA prenyltransferase family (Accession: PF01040) respectively. Potential risk variants and p.R22X shown in black were identified in multiple system atrophy (MSA) [4, 13, 17]. p.R22X only exists on the longest isoform, COQ2-001, and does not associated with MSA. †ENST00000439031 was missing in the latest Ensembl release 77 - October 2014. *Asterisks indicate variants found in our MSA series. Arrow shows an intronic variant, c403 + 10G > T (Exon1 + 10). Mutations in blue were identified in primary coenzyme Q10 (CoQ10) deficiency [5–12]. Mutations in red (p.S146N, p.R197H and p.R387X) were identified both in MSA and primary CoQ10 deficiency [4, 6, 8, 13].
Mentions: In this study, our sequence analysis of COQ2 in 155 MSA patients identified eleven variants including one intronic, six synonymous, three non-synonymous and one nonsense variants (Table 1), however exon dosage assays did not detect any deletion/multiplication. Four variants are common, p.R22X, p.L66V, p.D298D and p.S330S, and present in the Exome Variant Server (EVS) and 1000 Genomes; there was no significant minor allele frequency (MAF) difference with our patients, EVS data, or 1000 Genomes data (Table 1; Additional file 1). 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 EVS data or 1000 Genomes data (Table 1; Additional file 1). This variant is incorporated into one of the longer COQ2 transcripts (Figure 1); given the frequency of this variant and the presence of homozygotes both in our study and the EVS, it is unlikely this variant is of clinical relevance in primary CoQ10 deficiency or MSA. Indeed, Schottlaender and Houlden recently reported that p.R22X was more common in controls than cases [13].Table 1

Bottom Line: Loss of function COQ2 mutations results in primary CoQ10 deficiency.We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ross.owen@mayo.edu.

ABSTRACT

Background: 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). 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.

Results: We 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.

Conclusions: The 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.

Show MeSH
Related in: MedlinePlus