Very large (CAG)n DNA repeat expansions in the sperm of two spinocerebellar ataxia type 7 males
Very large (CAG)n DNA repeat expansions in the sperm of two spinocerebellar ataxia type 7 males
复制标题
DOI：
10.1093/hmg/8.13.2473
复制
发表时间：
1999-12-01
影响因子：
3.5
通讯作者：
Ashizawa, T
中科院分区：
文献类型：
--
作者：
Monckton, DG;Cayuela, ML;Ashizawa, T
在许多疾病中观察到遗传预测，即从一代到下一代增加疾病严重性和降低发病年龄，包括1型肌强直性营养不良、亨廷顿病和几种脊髓小脑共济失调。所有这些疾病都与三核苷酸重复序列的扩增有关，并且阵列长度与疾病严重性正相关，与发病年龄负相关。扩展的重复序列是高度不稳定的，并继续从一代扩展到下一代，为预期提供了分子解释。脊髓小脑性共济失调7型（SCA7）是最新加入的三联重复疾病列表中的一种，并且与其他SCA的不同之处在于其伴有视网膜变性。谱系分析先前已经揭示SCA7重复是高度不稳定的并且易于扩展，特别是当由男性传播时。然而，令人惊讶的是，也有报告称男性传播的代表性不足。我们现在通过单分子分析直接证明，扩增的重复序列在男性生殖系中非常不稳定，并且偏向于大量增加。两个SCA7雄性的几乎所有突变精子都含有如此大的等位基因，以至于大多数受影响的后代充其量只能患上严重的婴儿型疾病。事实上，这种非常大的扩增等位基因在患者中的总体代表性不足表明，相当大比例的这种等位基因可能与胚胎致死或精子功能障碍有关。
Genetic anticipation, i.e. increasing disease severity and decreasing age of onset from one generation to the next, is observed in a number of diseases, including myotonic dystrophy type 1, Huntington's disease and several of the spinocerebellar ataxias, All of these disorders are associated with the expansion of a trinucleotide repeat and array length is positively correlated with disease severity and inversely correlated with the age of onset, The expanded repeat is highly unstable and continues to expand from one generation to the next, providing a molecular explanation for anticipation. Spinocerebellar ataxia type 7 (SCA7) is one of the latest additions to the list of triplet repeat diseases and is distinct from the other SCAs in that it is accompanied by retinal degeneration, Pedigree analyses have previously revealed that the SCA7 repeat is highly unstable and liable to expand, in particular when transmitted by a male. Surprisingly, though, an under-representation of male transmission has also been reported. We now demonstrate directly by single molecule analyses that the expanded repeat is extraordinarily unstable in the male germline and biased toward massive increases. Nearly all of the mutant sperm of two SCA7 males contain alleles that are so large that most of the affected offspring would at best have a severe infantile form of the disease. Indeed, the gross under-representation of such very large expanded alleles in patients suggests that a significant proportion of such alleles might be associated with embryonic lethality or dysfunctional sperm.