Unusually Severe Heterozygous β-Thalassemia: Evidence for an Interacting Gene Affecting Globin Translation
Unusually Severe Heterozygous β-Thalassemia: Evidence for an Interacting Gene Affecting Globin Translation
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异常严重的杂合性 β-地中海贫血：影响球蛋白翻译的相互作用基因的证据
DOI：
10.1182/blood.v92.9.3428.421k05_3428_3435
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发表时间：
1998
期刊：
影响因子：
20.3
通讯作者：
S. Thein
中科院分区：
文献类型：
--
作者：
By P. Joy Ho;Georgina W. Hall;Suzanne Watt;N. West;J. Wimperis;William G. Wood;S. Thein
亚洲人群中常见的β-地中海贫血突变是2内含子654位的C→T替换，这导致两个隐剪接位点被激活，并且在突变mRNA中掺入了73个额外的核苷酸。像大多数β-地中海贫血突变一样，它通常表现为隐性遗传。我们研究了这种突变的两个杂合子的异常严重表型，父亲和儿子，他们患有地中海贫血中间和明显的显性遗传模式。与无症状的β654杂合子相比，先证者网织细胞中异常剪接转录物的水平增加，这促使我们研究β654 RNA的产生和加工。我们发现在一个无症状病例的红母细胞中检测到大量的异常β654转录物。这种mRNA的翻译产物在体内无法检测到，并且我们无法证明突变mRNA在无细胞翻译系统中的翻译。虽然两个先证者的网织红细胞：β mRNA比值在无症状杂合子中观察到的范围内，但珠蛋白链生物合成研究表明，先证者的：β链失衡程度要大得多。这些结果表明，更严重的表型可能是由于第二种缺陷，可能与β-珠蛋白簇无关，在翻译或翻译后水平起作用。
A common β-thalassemia mutation in Asian populations is the C → T substitution at position 654 of intron 2, which leads to the activation of two cryptic splicing sites and the incorporation of 73 extra nucleotides into the mutant mRNA. Like most β-thalassemia mutations, it normally exhibits recessive inheritance. We investigated the unusually severe phenotype in two heterozygotes for this mutation, father and son, who had thalassemia intermedia and an apparent dominant mode of inheritance. An increased level of aberrantly spliced transcript in the reticulocytes of the probands compared with asymptomatic β654heterozygotes led us to investigate the production and processing of β654 RNA. We showed that large amounts of the aberrant β654 transcript were detectable in erythroblasts from one of the asymptomatic cases. The translation product of this mRNA was not detectable in vivo, and we were unable to demonstrate the translation of the mutant mRNA in a cell-free translation system. Although the reticulocyte :β mRNA ratios in the two probands were within the range observed in the asymptomatic heterozygotes, globin chain biosynthesis studies showed that the probands had considerably greater :β chain imbalance. These results imply that the more severe phenotype may be due to a second defect, possibly unlinked to the β-globin cluster, that acts at the translational or posttranslational level.
© 1998 by The American Society of Hematology.
影响因子：
9.8
作者：
V. Chan;T. Chan;F. F. Chebab-F.;D. Todd
通讯作者：
V. Chan;T. Chan;F. F. Chebab-F.;D. Todd
DOI：
10.1073/pnas.94.6.2410
发表时间：
1997-03-18
影响因子：
11.1
作者：
Holcik, M;Liebhaber, SA
通讯作者：
Liebhaber, SA