Congenital erythropoietic porphyria: identification and expression of exonic mutations in the uroporphyrinogen III synthase gene.
Congenital erythropoietic porphyria: identification and expression of exonic mutations in the uroporphyrinogen III synthase gene.
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DOI：
10.1172/jci115637
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发表时间：
1992-02
期刊：
影响因子：
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通讯作者：
C. A. Warner;Han-Wook Yoo;Andrew W. Roberts;R. Desnick
中科院分区：
文献类型：
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作者：
C. A. Warner;Han-Wook Yoo;Andrew W. Roberts;R. Desnick
先天性红细胞生成性卟啉病（CEP）是一种血红素合成障碍性疾病，是由尿卟啉原III合酶（URO-合酶）活性缺陷引起的。这种常染色体隐性遗传疾病是异质性的;严重疾病的患者通常依赖输血，而轻度患者主要累及皮肤。为了研究这种表型异质性，在不相关的CEP患者中鉴定了URO合酶基因的外显子点突变。鉴定出4个错义突变：（a）核苷酸（nt）184的A到G的转换，预测第62位残基的Thr到Ala的取代（B）编码残基66处Ala至瓦尔置换的nt 197的C至T转变（A66 V）;（c）nt 217的T至C转变，其预测残基73处的Cys至Arg置换（C73 R）;和（d）nt 683的C至T转变，其导致残基228处的Thr至Met置换（T228 M）。此外，在一名非洲患者中检测到nt 27的G到A转换，其编码的氨基酸（A9 A）没有改变。T62 A、C73 R和T228 M等位基因不表达可检测的酶活性，而A66 V等位基因表达残余的但不稳定的活性。C73 R等位基因存在于21例无关CEP患者中的8例（占CEP等位基因的21%）。在3例患者中，两种等位基因的鉴定允许基因型-表型相关性; A66 V/C73 R、T228 M/C73 R和C73 R/C73 R基因型分别具有轻度、中度和重度疾病。这些发现提供了第一个基因型-表型相关性，并允许在这种遗传性卟啉症的分子杂合子检测。
Congenital erythropoietic porphyria (CEP), an inborn error of heme biosynthesis, results from the deficient activity of uroporphyrinogen III synthase (URO-synthase). This autosomal recessive disorder is heterogeneous; patients with severe disease are often transfusion dependent, while milder patients primarily have cutaneous involvement. To investigate this phenotypic heterogeneity, exonic point mutations in the URO-synthase gene were identified in unrelated CEP patients. Four missense mutations were identified: (a) an A to G transition of nucleotide (nt) 184 that predicted a Thr to Ala substitution at residue 62 (designated T62A); (b) a C to T transition of nt 197 that encoded an Ala to Val replacement at residue 66 (A66V); (c) a T to C transition of nt 217 that predicted a Cys to Arg substitution at residue 73 (C73R); and (d) a C to T transition of nt 683 that resulted in a Thr to Met replacement at residue 228 (T228M). In addition, a G to A transition of nt 27 that did not change the encoded amino acid (A9A) was detected in an African patient. The T62A, C73R, and T228M alleles did not express detectable enzymatic activity, while the A66V allele expressed residual, but unstable activity. The C73R allele was present in eight of 21 unrelated CEP patients (21% of CEP alleles). In three patients, identification of both alleles permitted genotype-phenotype correlations; the A66V/C73R, T228M/C73R, and C73R/C73R genotypes had mild, moderately severe, and severe disease, respectively. These findings provide the first genotype-phenotype correlations and permit molecular heterozygote detection in this inherited porphyria.