title: A large deletion on chromosome 11 in acute intermittent porphyria.
abstract: Acute intermittent porphyria (AIP) is an autosomal disorder caused by molecular abnormalities in the gene coding for hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. So far, more than 242 different mutations responsible for AIP have been identified in this gene. In an Italian family with typical clinical and biochemical signs of AIP, no mutation was found by direct sequencing of the entire hydroxymethylbilane synthase gene (HMBS). All the symptomatic patients showed apparent homozygosity and absence of mendelian segregation for eleven common polymorphisms along the gene. Excluding interference of polymorphisms in the primer sites, we assumed the presence of a complete HMBS gene deletion. In order to identify the size of this deletion, single nucleotide polymorphisms (SNPs) analysis was extended to flanking genes, H2A Histone Family member X (H2AFX) and Dolichyl-Phosphate N-Acetylglucosamine Phosphotransferase 1 (DPAGT1), downstream and Vacuolar protein sorting 11 (VPS11), upstream. Heterozygous polymorphisms in the VPS11 and DPAGT1 genes were found. Thus, we performed a Long-PCR with primers situated in regions outside the homozygous polymorphisms and we identified a double deletion with inversion on chromosome 11 (g22516974_22524062del7088, g22524062_22524278inv216, g22524278_22531093del6815). Even if the deletions include the entire HMBS and H2AFX genes and 1463 bp of the final portion of DPAGT1 gene, our patients had no other symptoms than AIP.
authors.affiliation: Department of Internal Medicine, Maggiore Policlinico, Mangiagalli and Regina Elena, Foundation IRCCS, University of Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Di Pierro
authors.forename: Valeria
authors.initials: V
authors.lastname: Besana
authors.forename: Valeria
authors.initials: V
authors.lastname: Moriondo
authors.forename: Valentina
authors.initials: V
authors.lastname: Brancaleoni
authors.forename: Dario
authors.initials: D
authors.lastname: Tavazzi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Casalgrandi
authors.forename: Paolo
authors.initials: P
authors.lastname: Ventura
authors.forename: Emilio
authors.initials: E
authors.lastname: Rocchi
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Cappellini
mesh_terms: D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D004252:DNA Mutational Analysis; D005192:Family Health; D006657:Histones / Q000235:genetics; D006720:Homozygote; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000235:genetics; D040582:Inheritance Patterns; D007558:Italy; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D011110:Polymorphism, Genetic; D017118:Porphyria, Acute Intermittent / Q000201:enzymology / Q000235:genetics*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D017351:N-Acetylglucosaminyltransferases; C047835:dolichyl-phosphate alpha-N-acetylglucosaminyltransferase; D011163:Hydroxymethylbilane Synthase