Martorell L, Monckton D G, Gamez J, Johnson K J, Gich I, Lopez de Munain A, Baiget M
Unitat de Genètica Molecular and Institut de Recerca, Hospital de Sant Pau, Pare Claret 167, 08025 Barcelona, Spain.
Hum Mol Genet. 1998 Feb;7(2):307-12. doi: 10.1093/hmg/7.2.307.
The genetic basis of myotonic dystrophy (DM) is the expansion of an unstable CTG repeat in the 34 UTR of the DM protein kinase gene on chromosome 19. One of the principal features of the DM mutation is an extraordinarily high level of somatic mosaicism, due to an extremely high degree of somatic instability both within and between different tissues. This instability appears to be biased towards further expansion and continuous throughout the life of an individual, features that could be associated with the progressive nature of the disease. Although increasing measured allele size between patients clearly correlates with an increased severity of symptoms and an earlier age of onset, this correlation is not precise and measured allele length cannot be used as an accurate predictor of age of onset. In order to further characterize the dynamics of DM CTG repeat somatic instability, we have studied repeat length changes over time in 111 myotonic dystrophy patients with varying clinical severity and CTG repeat size over time intervals of 1-7 years. We have found a direct progression of the size heterogeneity over time related to initial CTG repeat size and the time interval and always biased towards further expansion. Attempts to mathematically model the dynamics have proved only partially successful suggesting that individual specific genetic and/or environmental factors also play a role in somatic mosaicism.
强直性肌营养不良（DM）的遗传基础是19号染色体上DM蛋白激酶基因3′UTR中不稳定的CTG重复序列的扩增。DM突变的主要特征之一是体细胞嵌合现象极为严重，这是由于不同组织内部和之间都存在极高程度的体细胞不稳定性。这种不稳定性似乎倾向于进一步扩增，并且在个体的一生中持续存在，这些特征可能与疾病的进行性本质相关。虽然患者之间测量到的等位基因大小增加显然与症状严重程度增加和发病年龄提前相关，但这种相关性并不精确，测量到的等位基因长度不能用作发病年龄的准确预测指标。为了进一步描述DM中CTG重复序列体细胞不稳定性的动态变化，我们研究了111例临床严重程度不同且CTG重复序列大小各异的强直性肌营养不良患者在1至7年时间间隔内重复序列长度随时间的变化。我们发现，随着时间推移，大小异质性与初始CTG重复序列大小和时间间隔直接相关，并且始终倾向于进一步扩增。对这种动态变化进行数学建模的尝试仅取得了部分成功，这表明个体特异性的遗传和/或环境因素在体细胞嵌合现象中也发挥了作用。
