Haplotype analysis of families with erythropoietic protoporphyria and novel mutations of the ferrochelatase gene.
Haplotype analysis of families with erythropoietic protoporphyria and novel mutations of the ferrochelatase gene.
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DOI：
10.1046/j.1523-1747.1999.00637.x
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发表时间：
1999-07
期刊：
影响因子：
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通讯作者：
X. Wang;L. Yang;L. Kurtz;A. Lichtin;V. Deleo;J. Bloomer;M. Poh-Fitzpatrick
中科院分区：
文献类型：
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作者：
X. Wang;L. Yang;L. Kurtz;A. Lichtin;V. Deleo;J. Bloomer;M. Poh-Fitzpatrick
亚铁螯合酶，催化血红素生物合成途径中的末端步骤的酶，是人类遗传性疾病红细胞生成性原卟啉症中的缺陷位点。分子遗传学研究表明，大多数红细胞生成性原卟啉症病例以显性方式传播，并且红细胞生成性原卟啉症的基础突变是异质性的。我们进行了单倍型分析的美国家庭，共享经常性亚铁螯合酶基因突变，但有祖先来自几个欧洲国家。这是为了深入了解这些突变是否代表铁螯合酶基因的突变热点，或携带突变的祖先等位基因的繁殖。发现两个复发突变发生在独特的18号染色体单倍型上，与热点突变一致。另一方面，我们发现了三组两个不相关的家庭，共享相同的单倍型携带这些突变，这可能反映了祖先突变等位基因的地理分散。此外，我们报告了与红细胞生成性原卟啉症相关的新突变：外显子4供体位点的g（+ 1）-->t颠换，外显子6供体位点的g（+ 1）-->a转换，外显子9供体位点的t（+ 2）-->a置换;这些突变被预测会导致相关外显子的剪接缺陷。我们还在4个不相关的红细胞生成性原卟啉症家系中发现了外显子1供体位点的g（+ 5）-->a转换，在另一个家系中发现了外显子9供体位点的G（- 1）-->A替换。这些序列变化是正常多态性的可能性实际上被排除了（p < 0.0001），因为它们在30名正常受试者和30名有或没有已知突变的红细胞生成性原卟啉症患者的120个亚铁螯合酶等位基因中缺失。
Ferrochelatase, the enzyme that catalyzes the terminal step in the heme biosynthetic pathway, is the site of the defect in the human inherited disease erythropoietic protoporphyria. Molecular genetic studies have shown that the majority of erythropoietic protoporphyria cases are transmitted in dominant fashion and that mutations underlying erythropoietic protoporphyria are heterogeneous. We performed haplotype analysis of American families that shared recurrent ferrochelatase gene mutations yet had forbearers from several European countries. This was to gain insight into whether these mutations represent mutational hotspots at the ferrochelatase gene, or propagation of ancestral alleles bearing the mutations. Two recurrent mutations were found to occur on distinctive chromosome 18 haplotypes, consistent with being hotspot mutations. On the other hand, we found three sets of two unrelated families that shared the same haplotypes bearing these mutations, which could reflect geographic dispersion of ancestral mutant alleles. In addition, we report novel mutations associated with erythropoietic protoporphyria: g(+ 1)-->t transversion of the exon 4 donor site, g(+ 1)-->a transition of the exon 6 donor site, and t(+ 2)-->a substitution at the exon 9 donor site; these mutations are predicted to cause splicing defects of the associated exons. We also identified a g(+ 5)-->a transition of the exon 1 donor site in four unrelated families with erythropoietic protoporphyria, and a G(- 1)-->A substitution at the exon 9 donor site in an additional family. The probability that these sequence changes are normal polymorphisms was virtually excluded (p < 0.0001) by their absence in 120 ferrochelatase alleles from 30 normal subjects and 30 individuals with manifested erythropoietic protoporphyria with or without a known mutation.