Migraine, familial hemiplegic, 1; FHM1

Disease ID:627
Name:Migraine, familial hemiplegic, 1; FHM1
Associated with:1 target
Synonyms
Familial hemiplegic migraine | Familial or sporadic hemiplegic migraine
Database Links
Disease Ontology: DOID:0060178
OMIM: 141500
Orphanet: ORPHA569

Targets

Cav2.1
Comments:  The majority of FHM-1 mutations are located in the S4 voltage sensors and flanking regions. Examination of FHM-1 mutations on Cav2.1 biophysical properties using electrophysiological analysis in Xenopus laevis oocytes and HEK-293 cells shows considerable variability that may be accounted for by the use of different expression systems, Cav2.1 splice variants, auxiliary subunits and experimental conditions. Overall trends point towards FHM-1 mutations causing a predicted gain-of-function phenotype: shift of V0.5,act to more hyperpolarised potentials, increased availability of opening at lower membrane potentials, increased channel open probability and single channel conductance. Knock-in mice carrying R192Q and S218L FHM-1 mutations support gain-of-function in showing a lower threshold for stimulation of cortical spreading depression and increased velocity of propagation across the cortex, increased presynaptic basal calcium levels and altered synaptic plasticity. The severity of phenotype resulting from some FHM-1 mutations appears to be affected by CACNA1A alternative splicing.
References:  1-3
Mutations:  Cav2.1 is associated with 18 mutation. Click here for details

Ligands

No ligand related data available for Migraine, familial hemiplegic, 1; FHM1

References

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1. Adams PJ, Garcia E, David LS, Mulatz KJ, Spacey SD, Snutch TP. (2009) Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies. Channels (Austin), 3 (2): 110-21. [PMID:19242091]

2. Adams PJ, Rungta RL, Garcia E, van den Maagdenberg AM, MacVicar BA, Snutch TP. (2010) Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in the P/Q-type calcium channel. Proc. Natl. Acad. Sci. U.S.A., 107 (43): 18694-9. [PMID:20937883]

3. Adams PJ, Snutch TP. (2007) Calcium channelopathies: voltage-gated calcium channels. Subcell. Biochem., 45: 215-51. [PMID:18193639]

4. Barrett CF, Cao YQ, Tsien RW. (2005) Gating deficiency in a familial hemiplegic migraine type 1 mutant P/Q-type calcium channel. J. Biol. Chem., 280 (25): 24064-71. [PMID:15795222]

5. Cao YQ, Tsien RW. (2005) Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission. Proc. Natl. Acad. Sci. U.S.A., 102 (7): 2590-5. [PMID:15699344]

6. Carrera P, Piatti M, Stenirri S, Grimaldi LM, Marchioni E, Curcio M, Righetti PG, Ferrari M, Gelfi C. (1999) Genetic heterogeneity in Italian families with familial hemiplegic migraine. Neurology, 53 (1): 26-33. [PMID:10408532]

7. 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 (1): 17-24. [PMID:11439943]

8. Ducros A, Denier C, Joutel A, Vahedi K, Michel A, Darcel F, Madigand M, Guerouaou D, Tison F, Julien J, Hirsch E, Chedru F, Bisgård C, Lucotte G, Després 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 (1): 89-98. [PMID:9915947]

9. Gardner K, BernalO, Keegan M, Badger J, Gerber O, Lowry N, Hoffman EP. (1999) A new mutation in the Chr19p calcium channel gene CACNLIA4 causing hemiplegic migraine with ataxia. Neurology, 52 (suppl. 2): A115.

10. Hans M, Luvisetto S, Williams ME, Spagnolo M, Urrutia A, Tottene A, Brust PF, Johnson EC, Harpold MM, Stauderman KA, Pietrobon D. (1999) Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine. J. Neurosci., 19 (5): 1610-9. [PMID:10024348]

11. Kaja S, van de Ven RC, Broos LA, Veldman H, van Dijk JG, Verschuuren JJ, Frants RR, Ferrari MD, van den Maagdenberg AM, Plomp JJ. (2005) Gene dosage-dependent transmitter release changes at neuromuscular synapses of CACNA1A R192Q knockin mice are non-progressive and do not lead to morphological changes or muscle weakness. Neuroscience, 135 (1): 81-95. [PMID:16111830]

12. 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 (5): 684-8. [PMID:12756131]

13. Kors EE, Melberg A, Vanmolkot KR, Kumlien E, Haan J, Raininko R, Flink R, Ginjaar HB, Frants RR, Ferrari MD, van den Maagdenberg AM. (2004) Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation. Neurology, 63 (6): 1136-7. [PMID:15452324]

14. Kors EE, Terwindt GM, Vermeulen FL, Fitzsimons RB, Jardine PE, Heywood P, Love S, van den Maagdenberg AM, Haan J, Frants RR, Ferrari MD. (2001) Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Ann. Neurol., 49 (6): 753-60. [PMID:11409427]

15. Kraus RL, Sinnegger MJ, Glossmann H, Hering S, Striessnig J. (1998) Familial hemiplegic migraine mutations change alpha1A Ca2+ channel kinetics. J. Biol. Chem., 273 (10): 5586-90. [PMID:9488686]

16. Kraus RL, Sinnegger MJ, Koschak A, Glossmann H, Stenirri S, Carrera P, Striessnig J. (2000) Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2+) channel kinetics. J. Biol. Chem., 275 (13): 9239-43. [PMID:10734061]

17. Melliti K, Grabner M, Seabrook GR. (2003) The familial hemiplegic migraine mutation R192Q reduces G-protein-mediated inhibition of P/Q-type (Ca(V)2.1) calcium channels expressed in human embryonic kidney cells. J. Physiol. (Lond.), 546 (Pt 2): 337-47. [PMID:12527722]

18. Müllner C, Broos LA, van den Maagdenberg AM, Striessnig J. (2004) Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I alter Cav2.1 Ca2+ channel gating: evidence for beta-subunit isoform-specific effects. J. Biol. Chem., 279 (50): 51844-50. [PMID:15448138]

19. 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 (3): 543-52. [PMID:8898206]

20. Romaniello R, Zucca C, Tonelli A, Bonato S, Baschirotto C, Zanotta N, Epifanio R, Righini A, Bresolin N, Bassi MT et al.. (2010) A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation. J. Neurol. Neurosurg. Psychiatr., 81 (8): 840-3. [PMID:20682717]

21. Stam AH Vanmolkot KR Kremer HP Gärtner J Brown J Leshinsky-Silver E Gilad R Kors EE Frankhuizen WS Ginjaar HB Haan J Frants RR Ferrari MD van den Maagdenberg AM Terwindt GM. (2008) CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine. Clinical Genetics, Epub ahead of print (issue number): pages. [PMID:18400034]

22. Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, Pietrobon D. (2002) Familial hemiplegic migraine mutations increase Ca(2+) influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc. Natl. Acad. Sci. U.S.A., 99 (20): 13284-9. [PMID:12235360]

23. Tottene A, Pivotto F, Fellin T, Cesetti T, van den Maagdenberg AM, Pietrobon D. (2005) Specific kinetic alterations of human CaV2.1 calcium channels produced by mutation S218L causing familial hemiplegic migraine and delayed cerebral edema and coma after minor head trauma. J. Biol. Chem., 280 (18): 17678-86. [PMID:15743764]

24. Vahedi K, Denier C, Ducros A, Bousson V, Levy C, Chabriat H, Haguenau M, Tournier-Lasserve E, Bousser MG. (2000) CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology, 55 (7): 1040-2. [PMID:11061267]

25. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, Cesetti T, van de Ven RC, Tottene A, van der Kaa J, Plomp JJ, Frants RR, Ferrari MD. (2004) A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron, 41 (5): 701-10. [PMID:15003170]