title: Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes.
abstract: Mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na+,K+-ATPase, are associated with familial hemiplegic migraine type 2. The majority of ATP1A2 mutations were reported in patients with hemiplegic migraine without any additional neurological findings. Here, we report on two novel ATP1A2 mutations that were identified in two Portuguese probands with hemiplegic migraine and interesting additional clinical features. The proband's of family 1 (with a V362E mutation) had mood alterations, classified as a borderline personality. The proband in family 2 (with a P796S mutation) had mild mental impairment, in addition to hemiplegic migraine; more severe mental retardation was observed in his brother, who also had hemiplegic migraine and carried the same mutation. Cell-survival assays clearly showed abnormal functioning of mutant Na+,K+-ATPase, indicating that both ATP1A2 mutants are disease causing. Additionally, our results suggest a possible causal relationship of the ATP1A2 mutations with the complex clinical phenotypes observed in the probands.
authors.affiliation: Instituto de Ciências Biomédicas Abel Salazar, and UnIGENe, Instituto Biologia Molecular Celular, Universidade do Porto, Porto, Portugal.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Castro
authors.forename: B
authors.initials: B
authors.lastname: Nunes
authors.forename: B
authors.initials: B
authors.lastname: de Vries
authors.forename: C
authors.initials: C
authors.lastname: Lemos
authors.forename: K R J
authors.initials: KR
authors.lastname: Vanmolkot
authors.forename: J J M W
authors.initials: JJ
authors.lastname: van den Heuvel
authors.forename: T
authors.initials: T
authors.lastname: Temudo
authors.forename: J
authors.initials: J
authors.lastname: Barros
authors.forename: J
authors.initials: J
authors.lastname: Sequeiros
authors.forename: R R
authors.initials: RR
authors.lastname: Frants
authors.forename: J B
authors.initials: JB
authors.lastname: Koenderink
authors.forename: J M
authors.initials: JM
authors.lastname: Pereira-Monteiro
authors.forename: A M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D005192:Family Health; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020325:Migraine with Aura / Q000235:genetics*; D019964:Mood Disorders / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011174:Portugal; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*
chemical_list: C498531:ATP1A2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase