A novel recurrent mutation in ATP1A3 causes CAPOS syndrome

Abstract

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.

Conclusion: 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.

Figure 1

Pedigrees and Sanger sequencing results in three families with CAPOS syndrome. A) Pedigees. Family 1 was initially described by Nicolaides et al. [1] Individuals with CAPOS syndrome are indicated by filled pedigree symbols, and unaffected individuals, by empty symbols. B) Sanger sequencing results in affected and unaffected family members. A portion of the Sanger sequencing trace is shown for each individual who was tested, with the nucleotides at Ch19:47,166,267, corresponding to ATP1A3 position c.2452 on the minus strand, indicated by a vertical blue line. Each affected individual is heterozygous for the variant T (corresponding to c.2452A) and the reference C (corresponding to c.2452G) nucleotides. C) Conservation of Na⁺/K⁺ ATPase α₃ protein sequence in the region of the mutation. The E818K mutation found in all three CAPOS families is shown in red type; the location of the E815K loss-of-function mutation, which is associated with alternating hemiplegia of childhood, is shown in blue type. This segment of the Na⁺/K⁺ ATPase α₃ protein is highly conserved.