title: Molecular analysis of the hydroxymethylbilane synthase (HMBS) gene in Italian patients with acute intermittent porphyria: report of four novel mutations.
abstract: Acute intermittent porphyria (AIP) is an autosomal disorder caused by molecular abnormalities in the hydroxymethylbilane synthase (HMBS) gene coding for the third enzyme in the heme biosynthetic pathway. So far, more than 160 different mutations responsible for AIP have been identified in this gene. We have now identified seven mutations in eight unrelated Italian patients with AIP: two splicing defects (IVS7+2T-->C, 612G-->T), three small deletions (308-309delTG, 730-731delCT, 182delA) and two missense mutations (134C-->A, 541C-->T). The splicing defects were responsible for activation of splicing cryptic sites respectively within intron 7 (15 bp insertion) and exon 10 (9 bp deletion). The small deletions resulted in frameshifts leading to the formation of premature stop codons. The 134C-->A and 541C-->T mutations caused the formation of stop codons likely to be responsible for drastic disruption of the HMBS structure (Ser45Ter, Gln181Ter). This is the first molecular study in AIP patients of Italian origin leading to the identification of four new mutations and three molecular defects that have already been described.
authors.affiliation: Centro Anemie Congenite, Ospedale Maggiore Policlinico, IRCCS - Dipartimento di Medicina Interna, University of Milan, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Martinez di Montemuros
authors.forename: E
authors.initials: E
authors.lastname: Di Pierro
authors.forename: S
authors.initials: S
authors.lastname: Fargion
authors.forename: G
authors.initials: G
authors.lastname: Biolcati
authors.forename: D
authors.initials: D
authors.lastname: Griso
authors.forename: A
authors.initials: A
authors.lastname: Macrì
authors.forename: G
authors.initials: G
authors.lastname: Fiorelli
authors.forename: M D
authors.initials: MD
authors.lastname: Cappellini
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D005260:Female; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics*; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017118:Porphyria, Acute Intermittent / Q000201:enzymology* / Q000235:genetics*
chemical_list: D011163:Hydroxymethylbilane Synthase