Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in facioscapulohumeral muscular dystrophy
Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in facioscapulohumeral muscular dystrophy
复制标题
DOI：
10.1086/422175
复制
发表时间：
2004-07-01
影响因子：
9.8
通讯作者：
van der Maarel, SM
中科院分区：
文献类型：
--
作者：
Lemmers, RJLF;van Overveld, PGM;van der Maarel, SM
常染色体显性面肩肱型肌营养不良症（FSHD1A）与染色体4qter上多态性D4Z4重复序列的收缩相关。几乎一半的新FSHD突变发生在受精后，导致D4Z4的体细胞嵌合。详细的D4Z4分析11个嵌合体个体与FSHD揭示了嵌合体混合物的收缩FSHD大小的等位基因和不变的祖先等位基因在8例中，这是有丝分裂无交叉基因转换的暗示。然而，在3例病例中，D4Z4重排导致两个不同大小的D4Z4重复序列，表明存在交叉的基因转换。在所有的情况下，DNA标记的近端和远端D4Z4没有等位基因交换，这表明所有的重排染色体内。我们提出，D4Z4重排发生通过合成依赖的链退火模型，相对频繁地允许交叉。此外，FSHD嵌合体患者中不同细胞群的分布表明，嵌合体在受精后最初几次合子细胞分裂期间发生D4Z4重排。
Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1A) is associated with contractions of the polymorphic D4Z4 repeat on chromosome 4qter. Almost half of new FSHD mutations occur postfertilization, resulting in somatic mosaicism for D4Z4. Detailed D4Z4 analysis of 11 mosaic individuals with FSHD revealed a mosaic mixture of a contracted FSHD-sized allele and the unchanged ancestral allele in 8 cases, which is suggestive of a mitotic gene conversion without crossover. However, in 3 cases, the D4Z4 rearrangement resulted in two different-sized D4Z4 repeats, indicative of a gene conversion with crossover. In all cases, DNA markers proximal and distal to D4Z4 showed no allelic exchanges, suggesting that all rearrangements were intrachromosomal. We propose that D4Z4 rearrangements occur via a synthesis-dependent strand annealing model that relatively frequently allows for crossovers. Furthermore, the distribution of different cell populations in mosaic patients with FSHD suggests that mosaicism here results from D4Z4 rearrangements occurring during the first few zygotic cell divisions after fertilization.