Abstract
Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura. Three genes have been identified, all involved in ion transport. There is considerable clinical variation associated with FHM mutations. Genotype–phenotype correlation studies are needed, but are challenging mainly because the number of carriers of individual mutations is low. One exception is the recurrent T666M mutation in the FHM1 CACNA1A gene that was identified in almost one-third of FHM families and showed variable associated clinical features and severity, both within and among FHM families. Similar studies in the FHM2 ATP1A2 gene have not been performed because of the low number of carriers with individual mutations. Here we report on the recurrence of ATP1A2 mutations M731T and T376M that affect sodium–potassium pump functioning in two Portuguese FHM families. Considerably increasing the number of mutation carriers with these mutations indicated a clear genotype–phenotype correlation: both mutations are associated with pure FHM. In addition, we show that recurrent mutations for ATP1A2 are more frequent than previously thought, which has implications for genotype–phenotype correlations and genetic testing.
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References
Alonso I, Barros J, Tuna A, Coelho J, Sequeiros J, Silveira I, Coutinho P (2003) Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family. Arch Neurol 60:610–614
Ambrosini A, D’Onofrio M, Grieco GS, Di Mambro A, Montagna G, Fortini D, Nicoletti F, Nappi G, Sances G, Schoenen J, Buzzi MG, Santorelli FM, Pierelli F (2005) Familial basilar migraine associated with a new mutation in the ATP1A2 gene. Neurology 65:1826–1828
Bassi MT, Bresolin N, Tonelli A, Nazos K, Crippa F, Baschirotto C, Zucca C, Bersano A, Dolcetta D, Boneschi FM, Barone V, Casari G (2004) A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. J Med Genet 41:621–628
Battistini S, Stenirri S, Piatti M, Gelfi C, Righetti PG, Rocchi R, Giannini F, Battistini N, Guazzi GC, Ferrari M, Carrera P (1999) A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology 53:38–43
Capendeguy O, Horisberger JD (2004) Functional effects of Na+,K+-ATPase gene mutations. Neuromol Med 6:105–116
De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L, Ballabio A, Aridon P, Casari G (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 33:192–196
DeWitt ND, dos Santos CF, Allen KE, Slayman CW (1998) Phosphorylation region of the yeast plasma-membrane H+-ATPase. Role in protein folding and biogenesis. J Biol Chem 273:21744–21751
Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, Ferrari MD, Herzog J, van den Maagdenberg AM, Pusch M, Strom TM (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366:371–377
Ducros A, Joutel A, Vahedi K, Cecillon M, Ferreira A, Bernard E, Verier A, Echenne B, Lopez de Munain A, Bousser MG, Tournier-Lasserve E (1997) Mapping of a second locus for familial hemiplegic migraine to 1q21–q23 and evidence of further heterogeneity. Ann Neurol 42:885–890
Ducros A, Denier C, Joutel A, Vahedi K, Michel A, Darcel F, Madigand M, Guerouaou D, Tison F, Julien J, Hirsch E, Chedru F, Bisgard C, Lucotte G, Despres P, Billard C, Barthez MA, Ponsot G, Bousser MG, Tournier-Lasserve E (1999) Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. Am J Hum Genet 64:89–98
Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, Darcel F, Vicaut E, Bousser MG, Tournier-Lasserve E (2001) The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 345:17–24
Friend KL, Crimmins D, Phan TG, Sue CM, Colley A, Fung VS, Morris JG, Sutherland GR, Richards RI (1999) Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. Hum Genet 105:261–265
Headache Classification Subcommittee of the International Headache Society (2004) The International Classification of Headache Disorders, 2nd edition. Cephalalgia 24(Suppl 1):9–160
Jorgensen PL, Nielsen JM, Rasmussen JH, Pedersen PA (1998) Structure-function relationships of E1–E2 transitions and cation binding in Na,K-pump protein. Biochim Biophys Acta 1365:65–70
Jouvenceau A, Eunson LH, Spauschus A, Ramesh V, Zuberi SM, Kullmann DM, Hanna MG (2001) Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. Lancet 358:801–807
Jurkat-Rott K, Freilinger T, Dreier JP, Herzog J, Gobel H, Petzold GC, Montagna P, Gasser T, Lehmann-Horn F, Dichgans M (2004) Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants. Neurology 62:1857–1861
Kaunisto MA, Harno H, Vanmolkot KR, Gargus JJ, Sun G, Hamalainen E, Liukkonen E, Kallela M, van den Maagdenberg AM, Frants RR, Farkkila M, Palotie A, Wessman M (2004) A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2. Neurogenetics 5:141–146
Koenderink JB, Zifarelli G, Qiu LY, Schwarz W, De Pont JJ, Bamberg E, Friedrich T (2005) Na,K-ATPase mutations in familial hemiplegic migraine lead to functional inactivation. Biochim Biophys Acta 1669:61–68
Kors EE, Haan J, Giffin NJ, Pazdera L, Schnittger C, Lennox GG, Terwindt GM, Vermeulen FL, Van den Maagdenberg AM, Frants RR, Ferrari MD (2003) Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine. Arch Neurol 60:684–688
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87:543–552
Pierelli F, Grieco GS, Pauri F, Pirro C, Fiermonte G, Ambrosini A, Costa A, Buzzi MG, Valoppi M, Caltagirone C, Nappi G, Santorelli FM (2006) A novel ATP1A2 mutation in a family with FHM type II. Cephalalgia 26:324–328
Pressley TA (1992) Phylogenetic conservation of isoform-specific regions within alpha-subunit of Na(+)-K(+)-ATPase. Am J Physiol 262:C743–C751
Price EM, Rice DA, Lingrel JB (1990) Structure-function studies of Na,K-ATPase. Site-directed mutagenesis of the border residues from the H1–H2 extracellular domain of the alpha subunit. J Biol Chem 265:6638–6641
Riant F, De Fusco M, Aridon P, Ducros A, Ploton C, Marchelli F, Maciazek J, Bousser MG, Casari G, Tournier-Lasserve E (2005) ATP1A2 mutations in 11 families with familial hemiplegic migraine. Hum Mutat 26:281–287
Segall L, Mezzetti A, Scanzano R, Gargus JJ, Purisima E, Blostein R (2005) Alterations in the alpha2 isoform of Na,K-ATPase associated with familial hemiplegic migraine type 2. Proc Natl Acad Sci USA 102:11106–11111
Spadaro M, Ursu S, Lehmann-Horn F, Liana V, Giovanni A, Paola G, Frontali M, Jurkat-Rott K (2004) A G301R Na+/K+-ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. Neurogenetics 5:177–185
Swoboda KJ, Kanavakis E, Xaidara A, Johnson JE, Leppert MF, Schlesinger-Massart MB, Ptacek LJ, Silver K, Youroukos S (2004) Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol 55:884–887
Terwindt G, Kors E, Haan J, Vermeulen F, Van den Maagdenberg A, Frants R, Ferrari M (2002) Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Arch Neurol 59:1016–1018
Toyoshima C, Nakasako M, Nomura H, Ogawa H (2000) Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 A resolution. Nature 405:647–655
Vanmolkot KR, Kors EE, Hottenga JJ, Terwindt GM, Haan J, Hoefnagels WA, Black DF, Sandkuijl LA, Frants RR, Ferrari MD, van den Maagdenberg AM (2003) Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. Ann Neurol 54:360–366
Vanmolkot KR, Stroink H, Koenderink JB, Kors EE, van den Heuvel JJ, van den Boogerd EH, Stam AH, Haan J, De Vries BB, Terwindt GM, Frants RR, Ferrari MD, van den Maagdenberg AM (2006) Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation. Ann Neurol 59:310–314
Acknowledgments
We would like to thank Dr A. Levy Gomes for referring the proband of family 2 to us. We are particularly grateful to both Portuguese families for their participation and contribution for this study. The European Community provided financial support for this work, through a Marie-Curie grant for PhD students (M.-J.C, R.R.F.; contract no QLGA-CT-2000-60005), the “EUROHEAD” grant (LSHM-CT-2004-504837; R.R.F., M.D.F., A.M.J.M.vdM.), and Center of Medical System Biology (CMSB) established by The Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO).
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Castro, MJ., Stam, A.H., Lemos, C. et al. Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine. J Hum Genet 52, 990–998 (2007). https://doi.org/10.1007/s10038-007-0205-7
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DOI: https://doi.org/10.1007/s10038-007-0205-7
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