A universal mechanism ties genotype to phenotype in trinucleotide diseases.
A universal mechanism ties genotype to phenotype in trinucleotide diseases.
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DOI：
10.1371/journal.pcbi.0030235
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发表时间：
2007-11
影响因子：
4.3
通讯作者：
Shapiro E
中科院分区：
文献类型：
--
作者：
Kaplan S;Itzkovitz S;Shapiro E
三核苷酸遗传性疾病，如亨廷顿病和Friedreich共济失调，是与遗传基因中异常大量的DNA三核苷酸重复有关的无法治愈的疾病。与不同疾病相关的基因是不相关的，并且在不同的功能区含有三核苷酸重复；因此，令人惊讶的是，许多这些疾病的基因型之间具有相似的相关性，即遗传重复数与发病和进展的年龄表型。尽管进行了十多年的研究，但这些相关性仍然没有得到解释。尽管已经提出了几种三核苷酸疾病的机制，但没有一种建议是针对特定疾病的，无法解释这些疾病之间的共性。在这里，我们提出了一种普遍的机制，在这种机制中，依赖于长度的体细胞重复扩展发生在患者的一生中，接近病理阈值。我们的机制首次统一地解释了三核苷酸疾病常见的基因型-表型相关性，并得到了实验和临床数据的良好支持。此外，对发病机制的数学分析为一系列现象提供了简单的解释，如发病年龄曲线呈指数下降，具有纯合子突变和杂合突变的亨廷顿病患者的发病相似但进展更快，发病年龄与Friedreich共济失调患者的短等位基因长度相关，但与长等位基因无关。如果我们提出的普遍机制被证明是特定三核苷酸疾病实际机制的核心组成部分，它将开启对所有这些疾病的统一治疗的探索，可能通过推迟体细胞扩张过程。三核苷酸疾病是一个广泛的遗传性疾病家族，其遗传学特征是由重复的三个字母密码组成的DNA区域扩大。继承这种异常DNA区域的患者会在与扩大区域的大小成反比的年龄突然发病，随后是不可避免的和高度可预测的痛苦和死亡。尽管进行了十多年的研究，但这些疾病的潜在机制仍然是一个谜。尽管与各种三核苷酸疾病有关的基因是无关的，而且这些基因中的缺陷出现在编码该基因的DNA的不同部分，但这些疾病的共同特征表明，它们的根本原因是一个共同的机制。我们建议了一种机制，统一解释遗传DNA重复如何在基因上编码三核苷酸疾病的发病时间和进展速度。提示该病是通过遗传性异常扩增的DNA区域进一步扩大而表现和进展的。它解释了这个家族中许多疾病的临床数据，包括以前无法解释的与发病相关的现象。它还预测，这些疾病的一般治疗方法将是一种成功地干扰疾病三核苷酸重复序列持续扩大的药物或程序。
Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in different functional regions; therefore, it is striking that many of these diseases have similar correlations between their genotype, namely the number of inherited repeats and age of onset and progression phenotype. These correlations remain unexplained despite more than a decade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of the proposals, being disease-specific, can account for the commonalities among these diseases. Here, we propose a universal mechanism in which length-dependent somatic repeat expansion occurs during the patient's lifetime toward a pathological threshold. Our mechanism uniformly explains for the first time to our knowledge the genotype–phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data. In addition, mathematical analysis of the mechanism provides simple explanations to a wide range of phenomena such as the exponential decrease of the age-of-onset curve, similar onset but faster progression in patients with Huntington disease with homozygous versus heterozygous mutation, and correlation of age of onset with length of the short allele but not with the long allele in Friedreich ataxia. If our proposed universal mechanism proves to be the core component of the actual mechanisms of specific trinucleotide diseases, it would open the search for a uniform treatment for all these diseases, possibly by delaying the somatic expansion process. Trinucleotide diseases are a broad family of hereditary diseases characterized genetically by an expanded DNA region consisting of a repeated three-letter code. Patients inheriting such an abnormal DNA region experience sudden disease onset at an age that inversely depends on the size of the expanded region, followed by inevitable and highly predictable suffering and death. Despite more than a decade of research, the underlying mechanism of these diseases remains an enigma. Although the genes implicated with the various trinucleotide diseases are unrelated, and the defects in these genes occur in different parts of the DNA coding for the gene, the diseases' shared characteristics suggest a common mechanism underlies their root cause. We suggest a mechanism that uniformly explains how the inherited DNA repeats genetically encode the time of onset and the rate of progression of trinucleotide diseases. It suggests the disease manifests and progresses through the further expansion of the inherited abnormally expanded DNA region. It explains the clinical data of many diseases in this family, including previously unexplained onset-related phenomena. It also predicts that a general therapy for these diseases would be a drug or procedure that successfully interferes with the ongoing expansion of the disease trinucleotide repeat.
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