Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease.
Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease.
复制标题
DOI：
--
复制
发表时间：
1995-09
影响因子：
9.8
通讯作者：
N. Ranen;Colin Stine;Margaret H. Abbott;M. Sherr;'. A. Codori;M. Franz;'. Nientzu;'. A. S. Chung;N. Pleasant;Colleen Callahan;L. Kasch;Manely Ghaffari;Gary A. Chase;H. Kazazian;Jason Brandt;S. Folstein;Christopher A. Ross
中科院分区：
文献类型：
--
作者：
N. Ranen;Colin Stine;Margaret H. Abbott;M. Sherr;'. A. Codori;M. Franz;'. Nientzu;'. A. S. Chung;N. Pleasant;Colleen Callahan;L. Kasch;Manely Ghaffari;Gary A. Chase;H. Kazazian;Jason Brandt;S. Folstein;Christopher A. Ross
亨廷顿病（HD）是由4号染色体上的基因（IT-15）中的扩增和不稳定的三核苷酸重复（CAG）n引起的常染色体显性遗传变性疾病。HD表现出遗传预测-在一个家系内连续几代发病较早。从基于人群的临床样本中，我们确定了具有扩展等位基因的父母-后代对，以检查三核苷酸重复的代际行为及其与预期的关系。我们发现，重复长度的变化与父亲和后代之间的发病年龄的变化显着相关。当受影响父母的扩展三重重复序列被中位数重复序列长度分开时，我们发现父源和母源重复序列越长，在传递上越不稳定。然而，与父系传播不同的是，在父系传播中，较长的扩展重复序列比较短的扩展重复序列显示出更大的净扩展，而在母系传播中，较长或较短的扩展重复序列的重复长度没有平均变化。我们还证实了重复长度和发病年龄之间的反比关系，较高频率的青少年发病的情况下所产生的父系传播，预期的父系传播的现象，和更大的扩展与父系传播的三核苷酸重复。逐步多元回归分析表明，除了重复长度的后代，发病年龄的受影响的父母和性别的受影响的父母的贡献显着的方差在发病年龄的后代。因此，除了三重重复序列长度，其他因素，这可能是环境因素，遗传因素，或两者兼而有之，有助于发病年龄。我们的数据表明，进一步扩大受影响的范围内的父系重复提供了一个生物学基础的预期在HD。
Huntington disease (HD) is an autosomal dominant degenerative disorder caused by an expanded and unstable trinucleotide repeat (CAG)n in a gene (IT-15) on chromosome 4. HD exhibits genetic anticipation--earlier onset in successive generations within a pedigree. From a population-based clinical sample, we ascertained parent-offspring pairs with expanded alleles, to examine the intergenerational behavior of the trinucleotide repeat and its relationship to anticipation. We find that the change in repeat length with paternal transmission is significantly correlated with the change in age at onset between the father and offspring. When expanded triplet repeats of affected parents are separated by median repeat length, we find that the longer paternal and maternal repeats are both more unstable on transmission. However, unlike in paternal transmission, in which longer expanded repeats display greater net expansion than do shorter expanded repeats, in maternal transmission there is no mean change in repeat length for either longer or shorter expanded repeats. We also confirmed the inverse relationship between repeat length and age at onset, the higher frequency of juvenile-onset cases arising from paternal transmission, anticipation as a phenomenon of paternal transmission, and greater expansion of the trinucleotide repeat with paternal transmission. Stepwise multiple regression indicates that, in addition to repeat length of offspring, age at onset of affected parent and sex of affected parent contribute significantly to the variance in age at onset of the offspring. Thus, in addition to triplet repeat length, other factors, which could act as environmental factors, genetic factors, or both, contribute to age at onset. Our data establish that further expansion of paternal repeats within the affected range provides a biological basis of anticipation in HD.