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Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Cav2.1 causing episodic ataxia 2
  1. E Mantuano1,
  2. L Veneziano1,
  3. M Spadaro2,
  4. P Giunti6,
  5. S Guida1,
  6. M G Leggio3,
  7. L Verriello5,
  8. N Wood6,
  9. C Jodice4,
  10. M Frontali1
  1. 1Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy
  2. 2Department of Neurological Sciences, La Sapienza University, Rome, Italy
  3. 3Department of Psychology, La Sapienza University and IRCCS Fondazione Santa Lucia, Rome, Italy
  4. 4Department of Biology, Tor Vergata University, Rome, Italy
  5. 5Clinica Neurologica, DPMSC Udine University, Udine, Italy
  6. 6Institute of Neurology, University College, London, UK
  1. Correspondence to:
 Dr M Frontali
 INeMM-CNR, Via Fosso del Cavaliere, 00044 Frascati Rome, Italy; Marina.Frontaliims.rm.cnr.it

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Episodic ataxia type 2 (EA2, MIM 108500) is one of three allelic disorders due to mutations of the CACNA1A gene coding for the Cav2.1 subunit of P/Q type voltage gated Ca2+ channels. The other two allelic diseases are familial hemiplegic migraine (FHM, MIM 141500) and spinocerebellar ataxia type 6 (SCA6, MIM 183086). EA2 is characterised by a complex and highly variable phenotype, widely overlapping that of SCA6.1,2 Its main features are episodes of vertigo or ataxia of variable duration and frequency, a permanent cerebellar deficit of variable severity, sometimes progressive, and a cerebellar atrophy typically starting from the anterior portion of vermis. Recently dyskynesia,3 muscular weakness,4 and epilepsy5 have been described in association with EA2. FHM, on the other hand, is characterised by migraine attacks preceded by symptoms such as unilateral limb paresis or paralysis, paraesthesias, and dysphasia. Interictal cerebellar signs are reported in about 50% of patients.6

The CACNA1A gene product is the pore forming subunit of P/Q type Ca2+ channels, expressed in the brain and particularly in cerebellar Purkinje and granule cells, as well as in neuromuscular junctions.7,8 The protein is predicted to have four domains or repeats, each formed by six transmembrane hydrophobic segments (fig 1). Segments S5 and S6 of each domain line the pore region. The S5–S6 linkers are highly conserved sequences folded to leave their extremes in the extracellular space, and place within the pore a P sequence which exerts a critical role for ion selectivity and permeation of the Ca2+ channel.9

Figure 1

Predicted structure of the Cav 2.1 subunit of Ca2+ channels type P/Q and sites of non-truncating/disrupting (NTR) mutations causing EA2.

Point mutations in the CACNA1A gene are responsible for EA2 and FHM, whereas small expansions of …

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