The combination of episodic dysfunction and permanent deficit could depend on the variety of functions of calcium channels and their distribution in the nervous system.

Missense mutations in the pore-forming human ␣ 1A subunit of neuronal P/Q-type Ca 2؉ channels are associated with familial hemiplegic migraine. We studied the functional consequences on P/Q-type Ca 2؉ channel function of three recently identified mutations, R583Q, D715E, and V1457L after introduction into rabbit ␣ 1A and expression in Xenopus laevis oocytes. The potential for half-maximal channel activation of Ba 2؉ inward currents was shifted by > 9 mV to more negative potentials in all three mutants. The potential for half-maximal channel inactivation was shifted by > 7 mV in the same direction in R583Q and D715E. Biexponential current inactivation during 3-s test pulses was significantly faster in D715E and slower in V1457L than in wild type. Mutations R583Q and V1457L delayed the time course of recovery from channel inactivation. The decrease of peak current through R583Q (30.2%) and D715E (30.1%) but not V1457L (18.7%) was more pronounced during 1-Hz trains of 15 100-ms pulses than in wild type (18.2%). Our data demonstrate that the mutations R583Q, D715E, and V1457L, like the previously reported mutations T666M, V714A, and I1819L, affect P/Q-type Ca 2؉ channel gating. We therefore propose that altered channel gating represents a common pathophysiological mechanism in familial hemiplegic migraine.Voltage-gated P/Q-type Ca 2ϩ channels are expressed on cell bodies and dendrites of cerebellar Purkinje cells and other neurons (1-3) where they are thought to control neuronal excitability, gene expression, neuronal plasticity, and differentiation. These channels are also expressed on presynaptic terminals (3) mediating depolarization-induced Ca 2ϩ influx tightly coupled to neurotransmitter release (4). The Ca 2ϩ -selective pore of P/Q-type Ca 2ϩ channels is formed by ␣ 1A subunits, which also contain the voltage sensors. ␣ 1A is encoded by the human gene CACNA1A on chromosome 19p13 (5).P/Q-type Ca 2ϩ channels have received much attention recently because CACNA1A mutations have been described which are responsible for at least three different neurological human diseases: episodic ataxia type 2 (EA-2), 1 spinocerebellar ataxia type 6, and familial hemiplegic migraine (FHM) with and without cerebellar ataxia. These mutations may provide important insight into how altered Ca 2ϩ signaling and neuronal excitability can lead to neurodegeneration and episodic neurological diseases such as migraine.Four nonsense mutations (6 -8), three splice site mutations, and four deletions in CACNA1A (5, 7) have been found to segregate in patients with EA-2. Small CAG expansions were observed in a large series of patients with spinocerebellar ataxia type 6 (9), and a further CACNA1A missense mutation was identified in a patient with severe progressive ataxia (10). At least seven missense mutations have been identified in families with FHM (5, 11-13). Defects in the ␣ 1A gene are also responsible for the phenotypes (absence epilepsy and ataxia) of tottering (tg) and leaner (tg la ) mutant mice (14) and may also occur in more common for...

Genetic heterogeneity of FHM has been shown in familial and sporadic FHM patients of Italian origin. The new missense mutation-G4644T-is associated with milder clinical features compared with typical FHM.

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. According to the criteria adopted, the overall detection rate was 80% (352/440). Novel variants with uncertain significance were found in 14% of patients. Among patients with pathogenic variants, in 301 (85.5%) the disease is associated with PKD1, 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with PKD2. Our results outline the high allelic heterogeneity of variants, complicated by the presence of variants of uncertain significance as well as of multiple variants in the same subject. Classification of novel variants may be particularly cumbersome having an important impact on the genetic counselling. Our study confirms the importance to improve the assessment of variant pathogenicity for ADPKD; to this point databasing of both clinical and molecular data is crucial.