Familial hemiplegic migraine, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the α1A subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype—that is, T→C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human α1A-2 subunit, together with human β4 and α2δ subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.

Complete loss of P/Q calcium channel activity caused by CACNA1A missense mutation carried by episodic ataxia type 2 patients / Guida, S; Trettel, Flavia; Pagnutti, S; Mantuano, E; Tottene, A; Veneziano, L; Fellin, T; Spadaro, Maria; STAUDERMAN K., A; WILLIAMS M., E; Volsen, S; OPHOFF R., A; FRANTS R., R; Jodice, C; Frontali, M. AND PIETROBON D.. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - STAMPA. - 68:(2001), pp. 759-764. [10.1086/318804]

Complete loss of P/Q calcium channel activity caused by CACNA1A missense mutation carried by episodic ataxia type 2 patients.

TRETTEL, Flavia;SPADARO, Maria;
2001

Abstract

Familial hemiplegic migraine, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 are allelic disorders of the CACNA1A gene (coding for the α1A subunit of P/Q calcium channels), usually associated with different types of mutations (missense, protein truncating, and expansion, respectively). However, the finding of expansion and missense mutations in patients with EA2 has blurred this genotype-phenotype correlation. We report the first functional analysis of a new missense mutation, associated with an EA2 phenotype—that is, T→C transition of nt 4747 in exon 28, predicted to change a highly conserved phenylalanine residue to a serine at codon 1491, located in the putative transmembrane segment S6 of domain III. Patch-clamp recording in HEK 293 cells, coexpressing the mutagenized human α1A-2 subunit, together with human β4 and α2δ subunits, showed that channel activity was completely abolished, although the mutated protein is expressed in the cell. These results indicate that a complete loss of P/Q channel function is the mechanism underlying EA2, whether due to truncating or to missense mutations.
FAMILIAL HEMIPLEGIC MIGRAINE, CEREBELLAR-ATAXIA, MOLECULAR DETERMINANTS, CHROMOSOME 19P, GENE MUTATION, BLOCK, INACTIVATION, POLYMORPHISM, SUBUNIT, SCA6
01 Pubblicazione su rivista::01a Articolo in rivista
Complete loss of P/Q calcium channel activity caused by CACNA1A missense mutation carried by episodic ataxia type 2 patients / Guida, S; Trettel, Flavia; Pagnutti, S; Mantuano, E; Tottene, A; Veneziano, L; Fellin, T; Spadaro, Maria; STAUDERMAN K., A; WILLIAMS M., E; Volsen, S; OPHOFF R., A; FRANTS R., R; Jodice, C; Frontali, M. AND PIETROBON D.. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - STAMPA. - 68:(2001), pp. 759-764. [10.1086/318804]
File allegati a questo prodotto
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/142039
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 30
  • Scopus 135
  • ???jsp.display-item.citation.isi??? 108
social impact