Unusual association of a unique CAG interruption in 5′ of DM1 CTG repeats with intergenerational contractions and low somatic mosaicism

被引:28
作者
Tome, Stephanie [1 ,2 ]
Dandelot, Elodie [1 ,2 ]
Dogan, Celine [3 ]
Bertrand, Alexis [1 ,2 ]
Genevieve, David [4 ,5 ]
Pereon, Yann [6 ]
Simon, Marie [4 ]
Bonnefont, Jean-Paul [4 ]
Bassez, Guillaume [7 ]
Gourdon, Genevieve [1 ,2 ]
机构
[1] INSERM, Lab CTGDM, UMR1163, Paris, France
[2] Univ Paris 05, Sorbonne Paris Cite, Inst Imagine, F-75013 Paris, France
[3] Hop La Pitie Salpetriere, AP HP, Neuromuscular Reference Ctr, Paris, France
[4] Hop Necker Enfants Malad, Mol Genet Lab, Paris, France
[5] Univ Montpellier, CHU Montpellier, Dept Genet Med Malad Rares & Med Personnalisee, Montpellier, France
[6] Hop Hotel Dieu, Ctr Neuromuscular Dis, Nantes, France
[7] Sorbonne Univ, Hop Pitie Salpetriere, AP HP, INSERM,Neuromuscular Reference Ctr,UMRS974, F-75013 Paris, France
关键词
CTG contractions and 5 ' single CAG interruption; myotonic dystrophy type 1; triplet repeat instability; MYOTONIC-DYSTROPHY TYPE-1; SPINOCEREBELLAR ATAXIA; AGG INTERRUPTIONS; TRIPLET REPEATS; DNA-REPAIR; SEQUENCE INTERRUPTIONS; TRINUCLEOTIDE REPEATS; HEXANUCLEOTIDE REPEAT; DYNAMIC MUTATIONS; SKELETAL-MUSCLE;
D O I
10.1002/humu.23531
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 similar to 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.
引用
收藏
页码:970 / 982
页数:13
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