Puy H, Gross U, Deybach J C, Robréau A M, Frank M, Nordmann Y, Doss M
Centre Français des Porphyries, INSERM U409, Hôpital Louis Mourier, Colombes, France.
Hum Genet. 1998 Nov;103(5):570-5. doi: 10.1007/s004390050871.
Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial defect of the heme biosynthesis enzyme, porphobilinogen deaminase (PBGD). PBGD is encoded by two distinct mRNA species expressed in a tissue-specific manner from a single gene. One transcript is expressed in erythroid tissues, while the housekeeping transcript is expressed in all tissues. In classical AIP (95% of cases) the housekeeping and the erythroid-specific enzymes both have half-normal activity in erythroid and non-erythroid tissues, whereas in the variant non-erythroid form of the disease the enzymatic defect is present only in non-erythroid cells. A large allelic heterogeneity of mutations (n>135) has been demonstrated in classical AIP, but to date only three different mutations have been characterized in the non-erythroid variant form of AIP. We describe the molecular abnormalities responsible for the non-erythroid variant form of AIP in two French and two German unrelated AIP patients with normal PBGD activity in the erythrocytes. Three different splicing defects located in the intron 1 donor splice site were identified: a 33+1 g-->a mutation, previously described in a Dutch family, was found in two patients; two novel mutations (33+2 t-->a, 33+5 c-->g) affected the two remaining patients. All the mutations resulted in the activation of a cryptic splice site 67 bp downstream in intron 1, leading to a frameshift and a premature stop codon in exon 4. Mutations in the exon 1 donor splice site are involved in eight of the nine non-erythroid variant AIP families reported in the literature. These data show that most mutations causing the non-erythroid variant AIP are exon 1 splice defects, in contrast with classical AIP, where missense mutations are chiefly involved. Moreover, the allelic heterogeneity of PBGD gene defects causing the non-erythroid variant AIP is demonstrated, with five different mutations identified. These mutations could be easily detected by a single denaturing gradient gel electrophoresis which also allows the presymptomatic detection of gene carriers in the affected families.
急性间歇性卟啉病（AIP）是一种常染色体显性疾病，由血红素生物合成酶——胆色素原脱氨酶（PBGD）的部分缺陷引起。PBGD由单个基因以组织特异性方式表达的两种不同mRNA编码。一种转录本在红系组织中表达，而管家转录本在所有组织中表达。在典型AIP（95%的病例）中，管家酶和红系特异性酶在红系和非红系组织中的活性均为正常的一半，而在该疾病的非红系变异型中，酶缺陷仅存在于非红系细胞中。已证实在典型AIP中存在大量等位基因异质性突变（n>135），但迄今为止，在AIP的非红系变异型中仅鉴定出三种不同突变。我们描述了两名法国和两名德国不相关的AIP患者中导致AIP非红系变异型的分子异常，这些患者红细胞中的PBGD活性正常。在第1内含子供体剪接位点发现了三种不同的剪接缺陷：在两名患者中发现了一个33+1 g→a突变，该突变先前在一个荷兰家族中被描述；另外两名患者受两个新突变（33+2 t→a，33+5 c→g）影响。所有突变均导致第1内含子下游67 bp处一个隐蔽剪接位点的激活，导致移码和外显子4中的提前终止密码子。文献报道的9个非红系变异型AIP家族中有8个涉及外显子1供体剪接位点的突变。这些数据表明，与主要涉及错义突变的典型AIP相反，导致非红系变异型AIP的大多数突变是外显子1剪接缺陷。此外，已证实导致非红系变异型AIP的PBGD基因缺陷存在等位基因异质性，鉴定出了五种不同突变。这些突变可通过单一变性梯度凝胶电泳轻松检测，该方法还可对受影响家族中的基因携带者进行症状前检测。
