Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis.
Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis.
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DOI：
10.1371/journal.pgen.1004276
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发表时间：
2014-05
期刊：
影响因子：
4.5
通讯作者：
Akiyama M
中科院分区：
文献类型：
--
作者：
Ogawa Y;Takeichi T;Kono M;Hamajima N;Yamamoto T;Sugiura K;Akiyama M
当两种突变--一种是显性致病，另一种是“限制”的无稽之谈--共存于同一个等位基因时，从理论上讲，后者的逆转可能会引发疾病，比如潘多拉魔盒的打开。然而，这种假想致病机制的病例从未被报道过。我们描述了一种致命性的角膜炎-鱼鳞病-耳聋综合征(KID)综合征，由GJB2无义突变p.Tyr136X逆转引起，否则将限制另一个显性致命突变p.Gly45Glu在同一等位基因中的作用。患者的母亲有相同的错义突变，该突变受无义突变的限制。通过15个短串联重复序列基因座的基因分型，证实了亲子间的亲缘关系。单倍型分析使用了覆盖GJB2基因周围>；39KBP区域的40个SNP，以及覆盖整个13号染色体83,483个SNP的扩展SNP微阵列分析，结果表明，涉及携带突变的母体等位基因的等位基因重组事件产生了患者特有的致病等位基因，尽管不能完全排除自发点突变的巧合积累的可能性。以前的报道和我们的突变筛查都支持P.Gly45Glu与P.Tyr136X在日本人群中处于完全连锁不平衡。根据文献中的统计学估计，在日本人口中可能有大约11,000名P.Gly45Glu携带者具有这种第二位点限制性突变，这种突变起到了天然的遗传保护作用，免受这种致命疾病的侵袭。这项研究中显示的逆转触发的疾病发病是一种以前未报道的基于孟德尔遗传的遗传发病机制。无义突变导致的基因功能丧失是遗传病的一种典型致病机制。然而，在某些遗传背景下，它们可能会限制其他显性致病突变的影响，并抑制疾病表现。我们报告了文献中的第一例，GJB2基因“限制性”无义突变的逆转释放了共同存在的功能获得突变的显性致病效应，引发了致命的角膜炎-鱼鳞病-耳聋综合征(KID)。我们描述了由GJB2无义突变p.Tyr136X逆转引起的这种形式的KID综合征，否则将限制另一个显性致命突变p.Gly45Glu在同一等位基因中的作用。患者的母亲有相同的错义突变，该突变受无义突变的限制。一项流行病学估计表明，在日本人口中，大约有11,000人可能具有相同的致命GJB2突变，但由于他们也遗传了常见的“限制性”无义突变，因此不会出现这种综合征。这项研究中显示的逆转触发的疾病发病是一种以前未报道的基于孟德尔遗传的遗传发病机制。
When two mutations, one dominant pathogenic and the other “confining” nonsense, coexist in the same allele, theoretically, reversion of the latter may elicit a disease, like the opening of Pandora's box. However, cases of this hypothetical pathogenic mechanism have never been reported. We describe a lethal form of keratitis-ichthyosis-deafness (KID) syndrome caused by the reversion of the GJB2 nonsense mutation p.Tyr136X that would otherwise have confined the effect of another dominant lethal mutation, p.Gly45Glu, in the same allele. The patient's mother had the identical misssense mutation which was confined by the nonsense mutation. The biological relationship between the parents and the child was confirmed by genotyping of 15 short tandem repeat loci. Haplotype analysis using 40 SNPs spanning the >39 kbp region surrounding the GJB2 gene and an extended SNP microarray analysis spanning 83,483 SNPs throughout chromosome 13 in the family showed that an allelic recombination event involving the maternal allele carrying the mutations generated the pathogenic allele unique to the patient, although the possibility of coincidental accumulation of spontaneous point mutations cannot be completely excluded. Previous reports and our mutation screening support that p.Gly45Glu is in complete linkage disequilibrium with p.Tyr136X in the Japanese population. Estimated from statisitics in the literature, there may be approximately 11,000 p.Gly45Glu carriers in the Japanese population who have this second-site confining mutation, which acts as natural genetic protection from the lethal disease. The reversion-triggered onset of the disesase shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance. Loss of gene functions due to nonsense mutations is a typical pathogenic mechanism of hereditary diseases. They may, however, in certain genetic contexts, confine the effects of other dominant pathogenic mutations and suppress disease manifestations. We report the first instance in the literature where the reversion of a “confining” nonsense mutation in GJB2 gene released the dominant pathogenic effect of a coexsisting gain-of-function mutation, eliciting the lethal form of keratitis-ichthyosis-deafness syndrome (KID). We describe this form of KID syndrome caused by the reversion of the GJB2 nonsense mutation p.Tyr136X that would otherwise have confined the effect of another dominant lethal mutation, p.Gly45Glu, in the same allele. The patient's mother had the identical misssense mutation which was confined by the nonsense mutation. An epidemiologic estimation demonstrates that approximately 11,000 individuals in the Japanese population may have the same lethal GJB2 mutation, nonetheless protected from the manifestation of the syndrome because they also inherit the common “confining” nonsense mutation. The reversion-triggered onset of the disease shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance.
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影响因子：
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作者：
SKINNER, BA;GREIST, MC;NORINS, AL
通讯作者：
NORINS, AL
影响因子：
3.3
作者：
Mese G;Sellitto C;Li L;Wang HZ;Valiunas V;Richard G;Brink PR;White TW
通讯作者：
White TW
影响因子：
3.5
作者：
Sbidian, E.;Feldmann, D.;Hadj-Rabia, S.
通讯作者：
Hadj-Rabia, S.
影响因子：
64.8
作者：
Gibbs, RA;Belmont, JW;Tanaka, T
通讯作者：
Tanaka, T
DOI：
10.1126/science.1192280
发表时间：
2010-10-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Choate KA;Lu Y;Zhou J;Choi M;Elias PM;Farhi A;Nelson-Williams C;Crumrine D;Williams ML;Nopper AJ;Bree A;Milstone LM;Lifton RP
通讯作者：
Lifton RP