Clusters of non-truncating mutations of P/Q type Ca2+ channel subunit Cav2.1 causing episodic ataxia 2

Abstract

N Episodic ataxia type 2 (EA2) is mostly due to loss of function mutations that truncate or severely disrupt the pore forming (Cav2.1) subunit of P/Q type Ca2+ channels, coded by the CACNA1A gene. Gain of function missense mutations of the same gene are responsible for familial hemiplegic migraine. In a few cases, EA2 is due to mutations that do not truncate or disrupt the Cav2.1 subunit. N Screening for CACNA1A gene mutations was carried out for 27 patients with either typical EA2 or cerebellar ataxia of no known genetic type. N Five new Cav2.1 non-truncating/disrupting mutations were detected. From almost doubling the number of these mutations, it clearly emerges that they have a preferential location in specific protein regions, namely S5–S6 linkers and their borders. Their associated clinical phenotype is comparable with that reported for carriers of truncating/disrupting mutations, but data suggest a possible difference in age at onset and frequency of mental retardation. N The results show that EA2 mutations that do not truncate or disrupt the Cav2.1 subunit are not as rare as previously thought. Their associated phenotype might be less severe than that of truncating/disrupting mutations. They are clustered in highly conserved protein regions which may be particularly vulnerable to amino acid changes and are likely to have a critical role in the channel gating activity

Dominant-negative suppression of Cav2.1 currents by α12.1 truncations requires the conserved interaction domain for β subunits

“…The Ca v 2.1 calcium channel subtype regulates neurotransmission throughout the nervous system, but is predominantly expressed within cerebellar Purkinje cells (Usowicz et al, 1992;Stea et al, 1994;Westenbroek et al, 1995). Not surprisingly, cerebellar dysfunction is the primary feature of EA2 attacks, as patients experience bouts of symptoms such as ataxia, migraine and vertigo, in response to Functional expression studies involving EA2 mutations have firmly established that non-or hypo-conductive α 1 2.1 subunits cause the disorder (Guida et al, 2001;Jen et al, 2001;Jouvenceau et al, 2001;Wappl et al, 2002;Imbrici et al, 2004;Spacey et al, 2004;Imbrici et al, 2005;Wan et al, 2005b;Jeng et al, 2006), which is largely but not exclusively associated with expression of α 1 2.1 truncation mutants (Ophoff et al, 1996;Yue et al, 1998;Battistini et al, 1999;Denier et al, 1999;Jen et al, 1999;Denier et al, 2001;van den Maagdenberg et al, 2002;Wappl et al, 2002;Subramony et al, 2003;Jen et al, 2004;Mantuano et al, 2004;Eunson et al, 2005;Spacey et al, 2005;Wan et al, 2005a;Wan et al, 2005b;Scoggan et al, 2006). However, the molecular mechanisms by which nonfunctional α 1 2.1 pores generate disease in EA2 are still debated.…”

Infantile nystagmus and late onset ataxia associated with a CACNA1A mutation in the intracellular loop between s4 and s5 of domain 3

“…5 Other groups disagree. 12 However, the unusual clinical phenotype in this family may be due to the location of the mutation in part of the Ca(V)2.1 gene product.…”

“…4 The main features are episodes of vertigo or ataxia of variable frequency and duration, a permanent cerebellar deficit of variable severity, and a cerebellar atrophy typically starting from the anterior portion of the vermis. 5 Significant clinical overlap exists between these three disorders. …”

Novel missense variant of CACNA1A gene in a Slovak family with episodic ataxia type 2

“…12 ). Several missense variants in pore-loop regions have been described in the medical literature so far [12][13][14][15][16][17][18][19][20][21][22][23][24] . Structural changes in pore-loop regions can lead to functional changes disabling activation or inactivation of calcium flux 16 .…”