title: De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.
abstract: Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.
authors: Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
authors: Erin L
authors: EL
authors: Heinzen
authors: Kathryn J
authors: KJ
authors: Swoboda
authors: Yuki
authors: Y
authors: Hitomi
authors: Fiorella
authors: F
authors: Gurrieri
authors: Sophie
authors: S
authors: Nicole
authors: Boukje
authors: B
authors: de Vries
authors: F Danilo
authors: FD
authors: Tiziano
authors: Bertrand
authors: B
authors: Fontaine
authors: Nicole M
authors: NM
authors: Walley
authors: Sinéad
authors: S
authors: Heavin
authors: Eleni
authors: E
authors: Panagiotakaki
authors: Stefania
authors: S
authors: Fiori
authors: Emanuela
authors: E
authors: Abiusi
authors: Lorena
authors: L
authors: Di Pietro
authors: Matthew T
authors: MT
authors: Sweney
authors: Tara M
authors: TM
authors: Newcomb
authors: Louis
authors: L
authors: Viollet
authors: Chad
authors: C
authors: Huff
authors: Lynn B
authors: LB
authors: Jorde
authors: Sandra P
authors: SP
authors: Reyna
authors: Kelley J
authors: KJ
authors: Murphy
authors: Kevin V
authors: KV
authors: Shianna
authors: Curtis E
authors: CE
authors: Gumbs
authors: Latasha
authors: L
authors: Little
authors: Kenneth
authors: K
authors: Silver
authors: Louis J
authors: LJ
authors: Ptáček
authors: Joost
authors: J
authors: Haan
authors: Michel D
authors: MD
authors: Ferrari
authors: Ann M
authors: AM
authors: Bye
authors: Geoffrey K
authors: GK
authors: Herkes
authors: Charlotte M
authors: CM
authors: Whitelaw
authors: David
authors: D
authors: Webb
authors: Bryan J
authors: BJ
authors: Lynch
authors: Peter
authors: P
authors: Uldall
authors: Mary D
authors: MD
authors: King
authors: Ingrid E
authors: IE
authors: Scheffer
authors: Giovanni
authors: G
authors: Neri
authors: Alexis
authors: A
authors: Arzimanoglou
authors: Arn M J M
authors: AM
authors: van den Maagdenberg
authors: Sanjay M
authors: SM
authors: Sisodiya
authors: Mohamad A
authors: MA
authors: Mikati
authors: David B
authors: DB
authors: Goldstein
mesh_terms: D000328:Adult; D000818:Animals; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006429:Hemiplegia / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D017433:Protein Structure, Secondary; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase