Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 multiple osteochondromas families.
Breakpoint characterization of large deletions in EXT1 or EXT2 in 10 multiple osteochondromas families.
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DOI：
10.1186/1471-2350-12-85
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发表时间：
2011-06-26
影响因子：
--
通讯作者：
Wuyts W
中科院分区：
文献类型：
--
作者：
Jennes I;de Jong D;Mees K;Hogendoorn PC;Szuhai K;Wuyts W
骨软骨瘤（软骨帽骨肿瘤）是迄今为止所有原发性良性骨肿瘤中最常治疗的（50%）。在15%的病例中，这些肿瘤发生在称为多发性骨软骨瘤（MO）的遗传综合征的背景下，这是一种常染色体显性骨骼疾病，其特征是在儿童干骺端形成多发性软骨覆盖的骨肿瘤。MO是由EXT1或EXT2中的各种突变引起的，其中大的基因组缺失（单外显子或多外显子）导致高达8%的MO病例。在这里，我们报告的第一个分子特征的10个大的EXT1和EXT2缺失的MO患者。最初使用MLPA或FISH分析鉴定缺失，随后使用MO特异性平铺路径阵列、等位基因特异性PCR扩增和测序分析进行表征。在10个大缺失的组内，缺失区域范围为2.7至260 kb。发现1例EXT2外显子8缺失复发。所有断裂点均位于EXT1和EXT2的编码外显子之外。在不同的缺失中，假设由DNA序列介导的非等位基因同源重组（NAHR）、微同源介导的复制依赖性重组（MMRDR）和非同源末端连接（NHEJ）是致病机制。MO患者中EXT1和EXT2缺失断点的分子表征表明，NAHR序列之间以及NHEJ是因果关系，并且大多数这些缺失是非复发性的。这些观察结果再次强调了巨大的遗传变异性，这是MO的特征。据我们所知，这是第一项表征EXT1和EXT2中大基因组缺失的研究。
Osteochondromas (cartilage-capped bone tumors) are by far the most commonly treated of all primary benign bone tumors (50%). In 15% of cases, these tumors occur in the context of a hereditary syndrome called multiple osteochondromas (MO), an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped bone tumors at children's metaphyses. MO is caused by various mutations in EXT1 or EXT2, whereby large genomic deletions (single-or multi-exonic) are responsible for up to 8% of MO-cases. Here we report on the first molecular characterization of ten large EXT1- and EXT2-deletions in MO-patients. Deletions were initially indentified using MLPA or FISH analysis and were subsequently characterized using an MO-specific tiling path array, allele-specific PCR-amplification and sequencing analysis. Within the set of ten large deletions, the deleted regions ranged from 2.7 to 260 kb. One EXT2 exon 8 deletion was found to be recurrent. All breakpoints were located outside the coding exons of EXT1 and EXT2. Non-allelic homologous recombination (NAHR) mediated by Alu-sequences, microhomology mediated replication dependent recombination (MMRDR) and non-homologous end-joining (NHEJ) were hypothesized as the causal mechanisms in different deletions. Molecular characterization of EXT1- and EXT2-deletion breakpoints in MO-patients indicates that NAHR between Alu-sequences as well as NHEJ are causal and that the majority of these deletions are nonrecurring. These observations emphasize once more the huge genetic variability which is characteristic for MO. To our knowledge, this is the first study characterizing large genomic deletions in EXT1 and EXT2.
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DOI：
10.1016/j.tig.2008.08.007
发表时间：
2008-11
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
McVey M;Lee SE
通讯作者：
Lee SE
DOI：
10.2106/00004623-199407000-00005
发表时间：
1994-07-01
影响因子：
5.3
作者：
SCHMALE, GA;CONRAD, EU;RASKIND, WH
通讯作者：
RASKIND, WH
影响因子：
4.5
作者：
Han, Kyudong;Lee, Jungnam;Batzer, Mark A.
通讯作者：
Batzer, Mark A.
影响因子：
4.1
作者：
Jennes, Ivy;Entius, Mark M.;Wuyts, Wim
通讯作者：
Wuyts, Wim
DOI：
10.1302/0301-620x.45b2.292
发表时间：
1963-01-01
影响因子：
--
作者：
SOLOMON, L
通讯作者：
SOLOMON, L