Laboratory CTGDM, Inserm UMR1163, Paris, France; Institut Imagine, Université Paris-Descartes-Sorbonne Paris-Cité, Paris, France.
Neuromuscular Reference Center, AP-HP, Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
Hum Mutat. 2018 Jul;39(7):970-982. doi: 10.1002/humu.23531. Epub 2018 May 19.
Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. DM1 family pedigrees have shown that ∼90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions. A new and unique CAG interruption was found in 5' of the CTG expansion in one family, whereas multiple 5' CCG interruptions were detected in the second family. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood. By specific triplet-prime PCR, we observed that CTG repeat changes (contractions/expansions) occur preferentially in 3' of the interruptions for both families.
肌强直性营养不良 1 型（DM1）是一种显性多系统疾病，与症状和预期的高度可变性相关。DM1 是由不稳定的 CTG 重复扩展引起的，通常在连续几代和组织中增加。DM1 家族系谱表明，约 90%和 10%的传递分别导致 CTG 重复的扩展和收缩。迄今为止，DM1 中 CTG 重复收缩的机制仍记录不佳。在本报告中，我们鉴定了两个具有明显收缩且在两个和三个连续母系传递中 DM1 症状没有恶化的新 DM1 家族。在一个家族中，我们在 CTG 扩展的 5'端发现了一个新的和独特的 CAG 中断，而在第二个家族中检测到多个 5' CCG 中断。我们表明，这些中断与母系隔代收缩和血液中的低体细胞嵌合有关。通过特定的三核苷酸-引物 PCR，我们观察到对于两个家族，CTG 重复变化（收缩/扩展）优先发生在中断的 3'端。
