Analysis of COQ2 gene in multiple system atrophy.
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.
Kotaro
K
Ogaki
Shinsuke
S
Fujioka
Michael G
MG
Heckman
Sruti
S
Rayaprolu
Alexandra I
AI
Soto-Ortolaza
Catherine
C
Labbé
Ronald L
RL
Walton
Oswaldo
O
Lorenzo-Betancor
Xue
X
Wang
Yan
Y
Asmann
Rosa
R
Rademakers
Neill
N
Graff-Radford
Ryan
R
Uitti
William P
WP
Cheshire
Zbigniew K
ZK
Wszolek
Dennis W
DW
Dickson
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ross.owen@mayo.edu.
Owen A
OA
Ross
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019883:Alkyl and Aryl Transferases; C021386:4-hydroxybenzoate polyprenyltransferase