A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.
BACKGROUND
We undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome.


METHODS
We used whole-exome sequencing to analyze two families affected with CAPOS syndrome, including the original family reported in 1996, and Sanger sequencing to assess familial segregation of rare variants identified in the probands and in a third, apparently unrelated family with CAPOS syndrome.


RESULTS
We found an identical heterozygous missense mutation, c.2452G > A (p.(Glu818Lys)), in the Na⁺/K⁺ ATPase α₃(ATP1A3) gene in the proband and his affected sister and mother, but not in either unaffected maternal grandparent, in the first family. The same mutation was also identified in the proband and three other affected members of the second family and in all three affected members of the third family. This mutation was not found in more than 3600 chromosomes from unaffected individuals.


CONCLUSIONS
Other mutations in ATP1A3 have previously been demonstrated to cause rapid-onset dystonia-parkinsonism (also called dystonia-12) or alternating hemiplegia of childhood. This study shows that an allelic mutation in ATP1A3 produces CAPOS syndrome.
Division of Neurology, Department of Pediatrics, University of British Columbia and BC Children's Hospital, Vancouver, BC V6H 3N1, Canada. mdemos@cw.bc.ca.
Michelle K
MK
Demos
Clara Dm
CD
van Karnebeek
Colin Jd
CJ
Ross
Shelin
S
Adam
Yaoqing
Y
Shen
Shing Hei
SH
Zhan
Casper
C
Shyr
Gabriella
G
Horvath
Mohnish
M
Suri
Alan
A
Fryer
Steven Jm
SJ
Jones
Jan M
JM
Friedman
D000328:Adult; D002524:Cerebellar Ataxia / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000235:genetics*; D010375:Pedigree; D012021:Reflex, Abnormal / Q000235:genetics*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D055815:Young Adult
C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase