title: An intronic haplotype in α galactosidase A is associated with reduced mRNA expression in males with cryptogenic stroke.
abstract: Persons with unexplained early-onset stroke have been targeted for screening surveys for Fabry disease, the most common of the three X-linked lysosomal disorders, because Fabry patients with stroke are more likely to have the life-threatening progressive cardiac and renal manifestations and would therefore most benefit from early diagnosis and intervention with enzyme replacement therapy (ERT). Among 175 Israeli patients with unexplained cryptogenic stroke screened for mutations in the Fabry α galactosidase A (GLA) gene, sequencing identified six with 2-4 GLA intronic variants, one of whose father and three sisters had the same variants. Two variants, c.640-16A>G (g.10115A>G) in intron 4 and c.1000-22C>T (g.10956C>T) in intron 6, were common to all patients. However, three males with a common four variant intronic haplotype had low residual enzyme activity and ~50% reduced mRNA expression. Transcript splice-site defects were not identified in any of the index cases and X-chromosome inactivation was not highly skewed in the six females. These data do not suggest that GLA intronic variants, per se, are pathogenic. Nonetheless, it is clear that a certain intronic haplotype in males with cryptogenic stroke is associated with reduced GLA expression and function.
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Affiliated with the Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: David A
authors.initials: DA
authors.lastname: Zeevi
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Affiliated with the Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: Elinor
authors.initials: E
authors.lastname: Hakam-Spector
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Affiliated with the Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Herskovitz
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Affiliated with the Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Beeri
authors.affiliation: Gaucher Clinic, Shaare Zedek Medical Center, Affiliated with the Hadassah-Hebrew University School of Medicine, Jerusalem, Israel. Electronic address: elstein@szmc.org.il.
authors.forename: Deborah
authors.initials: D
authors.lastname: Elstein
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Affiliated with the Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: Gheona
authors.initials: G
authors.lastname: Altarescu
mesh_terms: D000328:Adult; D000368:Aged; D015536:Down-Regulation / Q000235:genetics; D000795:Fabry Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012737:Sex Factors; D020521:Stroke / Q000453:epidemiology / Q000235:genetics*; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D000519:alpha-Galactosidase
keywords: Early-onset stroke; Enzyme replacement therapy; Fabry disease; Intronic variants; X-linked recessive disorder; α galactosidase A