The CACNA1A gene, coding for the 1A-subunit (Cav2.1) of voltage-gated calcium channel type P/Q is responsible for Episodic Ataxia type 2 (EA2), Familial Hemiplegic Migraine (FHM) and Spinocerebellar Ataxia type 6 (SCA6). Several mutations causing these diseases have been described. In addition, families segregating for the disease with the CACNA1A, but not showing any mutations in the coding region, have also been found.Thirthy-four patients with typical EA2, and 8 with cerebellar ataxia of unknown genetic type, are screened for CACNA1A gene mutations. Four new Cav2.1 missense or non-truncating mutations and 1 truncating mutation have been detected. From an analysis of the localization of the non-truncating mutations together with those reported in literature it is further confirmed that: 1) they tend to be preferentially located in specific protein regions, namely S5-S6 linkers and their borders; 2) their associated clinical phenotype suggests a higher age at onset and a lower frequency of mental retardation. Families segregating for the disease with the CACNA1A markers, but not showing mutations of the coding region, suggest a further characterization of the gene. A new 3terminal exon, namely 48B, has been characterized. An alternative splice site about 300 bp upstream from 5end of exon 48 creates a so far unknown isoform similar to BI-1(V2.V3) but with a longer exon 48. Results from bioinformatic analysis show that the two isoforms with the alternatively spliced exon 48 have at least two different polyadenilation signal candidates. Since preliminary results suggest that mRNAs of this gene have dendritic localization and mRNA transport studies show a clear implication of the 3 tail in subcellular localization, these exons are being characterized both for the alternative polyadenilation signal usage and transport and for mutations causing disease in EA2 and cerebellar ataxia patients. Supported by grants MIUR cofin 2003 to CJ and FIRB2001, RBNE01XMP4-008, FISR2000 to MF.
Mutation analysis and regulating region characterization of CACNA1A gene coding for P/Q voltage-gated calcium channel 1A subunit.
E Mantuano;L Veneziano;S Guida;M Frontali
2004
Abstract
The CACNA1A gene, coding for the 1A-subunit (Cav2.1) of voltage-gated calcium channel type P/Q is responsible for Episodic Ataxia type 2 (EA2), Familial Hemiplegic Migraine (FHM) and Spinocerebellar Ataxia type 6 (SCA6). Several mutations causing these diseases have been described. In addition, families segregating for the disease with the CACNA1A, but not showing any mutations in the coding region, have also been found.Thirthy-four patients with typical EA2, and 8 with cerebellar ataxia of unknown genetic type, are screened for CACNA1A gene mutations. Four new Cav2.1 missense or non-truncating mutations and 1 truncating mutation have been detected. From an analysis of the localization of the non-truncating mutations together with those reported in literature it is further confirmed that: 1) they tend to be preferentially located in specific protein regions, namely S5-S6 linkers and their borders; 2) their associated clinical phenotype suggests a higher age at onset and a lower frequency of mental retardation. Families segregating for the disease with the CACNA1A markers, but not showing mutations of the coding region, suggest a further characterization of the gene. A new 3terminal exon, namely 48B, has been characterized. An alternative splice site about 300 bp upstream from 5end of exon 48 creates a so far unknown isoform similar to BI-1(V2.V3) but with a longer exon 48. Results from bioinformatic analysis show that the two isoforms with the alternatively spliced exon 48 have at least two different polyadenilation signal candidates. Since preliminary results suggest that mRNAs of this gene have dendritic localization and mRNA transport studies show a clear implication of the 3 tail in subcellular localization, these exons are being characterized both for the alternative polyadenilation signal usage and transport and for mutations causing disease in EA2 and cerebellar ataxia patients. Supported by grants MIUR cofin 2003 to CJ and FIRB2001, RBNE01XMP4-008, FISR2000 to MF.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
