Martinez di Montemuros F, Di Pierro E, Fargion S, Biolcati G, Griso D, Macrì A, Fiorelli G, Cappellini M D
Centro Anemie Congenite, Ospedale Maggiore Policlinico, IRCCS - Dipartimento di Medicina Interna, University of Milan, Milan, Italy.
Hum Mutat. 2000 May;15(5):480. doi: 10.1002/(SICI)1098-1004(200005)15:5<480::AID-HUMU12>3.0.CO;2-J.
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.
急性间歇性卟啉病（AIP）是一种常染色体疾病，由血红素生物合成途径中第三种酶——羟甲基胆色素合酶（HMBS）基因的分子异常引起。到目前为止，已在该基因中鉴定出160多种导致AIP的不同突变。我们现已在8名无亲缘关系的意大利AIP患者中鉴定出7种突变：2种剪接缺陷（IVS7+2T→C，612G→T）、3种小缺失（308-309delTG，730-731delCT，182delA）和2种错义突变（134C→A，541C→T）。这些剪接缺陷分别导致内含子7（15bp插入）和外显子10（9bp缺失）内的隐蔽剪接位点激活。小缺失导致移码，从而形成过早的终止密码子。134C→A和541C→T突变导致终止密码子的形成，可能导致HMBS结构的剧烈破坏（Ser45Ter，Gln181Ter）。这是对意大利裔AIP患者的首次分子研究，鉴定出了4种新突变和3种已被描述的分子缺陷。
