Exome sequencing and functional analysis identifies a novel mutation in EXT1 gene that causes multiple osteochondromas.
Exome sequencing and functional analysis identifies a novel mutation in EXT1 gene that causes multiple osteochondromas.
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外显子组测序和功能分析发现 EXT1 基因的新突变可导致多发性骨软骨瘤
DOI：
10.1371/journal.pone.0072316
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Zhang F;Liang J;Guo X;Zhang Y;Wen Y;Li Q;Zhang Z;Ma W;Dai L;Liu X;Yang L;Wang J
多发性骨软骨瘤（MO）是一种遗传性骨骼疾病，其分子机制尚不清楚。外显子组测序具有较高的染色体覆盖率和准确性，最近已成功用于鉴定致病基因突变。本研究首先采用外显子组测序和桑格测序验证的方法对一个中国家族的两个典型MO患者进行基因突变筛查。在过滤了来自1000基因组计划和dbSNP数据库（构建132）的数据后，通过对同一MO家族的其他四名成员和200名无关健康受试者的桑格测序进一步验证了检测到的候选基因突变。免疫组织化学和多序列比对进行评估的重要性，确定的因果突变。在EXT1基因第6外显子第486位密码子处发现一个新的移码突变c.1457insG，该突变导致EXT1基因糖基转移酶结构域截短。多序列比对结果表明，EXT1基因486密码子在不同脊椎动物中高度保守。免疫组化结果显示，MO中具有功能性EXT 1的软骨细胞少于遗传外孤立性软骨瘤。本研究报道的EXT1基因c.1457insG突变扩大了MO的致病突变谱，有助于MO的产前遗传筛查和早期诊断。
Multiple osteochondromas (MO) is an inherited skeletal disorder, and the molecular mechanism of MO remains elusive. Exome sequencing has high chromosomal coverage and accuracy, and has recently been successfully used to identify pathogenic gene mutations. In this study, exome sequencing followed by Sanger sequencing validation was first used to screen gene mutations in two representative MO patients from a Chinese family. After filtering the data from the 1000 Genome Project and the dbSNP database (build 132), the detected candidate gene mutations were further validated via Sanger sequencing of four other members of the same MO family and 200 unrelated healthy subjects. Immunohistochemisty and multiple sequence alignment were performed to evaluate the importance of the identified causal mutation. A novel frameshift mutation, c.1457insG at codon 486 of exon 6 of EXT1 gene, was identified, which truncated the glycosyltransferase domain of EXT1 gene. Multiple sequence alignment showed that codon 486 of EXT1 gene was highly conserved across various vertebrates. Immunohistochemisty demonstrated that the chondrocytes with functional EXT1 in MO were less than those in extragenetic solitary chondromas. The novel c.1457insG deleterious mutation of EXT1 gene reported in this study expands the causal mutation spectrum of MO, and may be helpful for prenatal genetic screening and early diagnosis of MO.
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影响因子：
64.8
作者：
Wu, Chi-Hong;Fallini, Claudia;Ticozzi, Nicola;Keagle, Pamela J.;Sapp, Peter C.;Piotrowska, Katarzyna;Lowe, Patrick;Koppers, Max;McKenna-Yasek, Diane;Baron, Desiree M.;Kost, Jason E.;Gonzalez-Perez, Paloma;Fox, Andrew D.;Adams, Jenni;Taroni, Franco;Tiloca, Cinzia;Leclerc, Ashley Lyn;Chafe, Shawn C.;Mangroo, Dev;Moore, Melissa J.;Zitzewitz, Jill A.;Xu, Zuo-Shang;van den Berg, Leonard H.;Glass, Jonathan D.;Siciliano, Gabriele;Cirulli, Elizabeth T.;Goldstein, David B.;Salachas, Francois;Meininger, Vincent;Rossoll, Wilfried;Ratti, Antonia;Gellera, Cinzia;Bosco, Daryl A.;Bassell, Gary J.;Silani, Vincenzo;Drory, Vivian E.;Brown, Robert H., Jr.;Landers, John E.
通讯作者：
Landers, John E.
影响因子：
64.8
作者：
Varela, Ignacio;Tarpey, Patrick;Raine, Keiran;Huang, Dachuan;Ong, Choon Kiat;Stephens, Philip;Davies, Helen;Jones, David;Lin, Meng-Lay;Teague, Jon;Bignell, Graham;Butler, Adam;Cho, Juok;Dalgliesh, Gillian L.;Galappaththige, Danushka;Greenman, Chris;Hardy, Claire;Jia, Mingming;Latimer, Calli;Lau, King Wai;Marshall, John;McLaren, Stuart;Menzies, Andrew;Mudie, Laura;Stebbings, Lucy;Largaespada, David A.;Wessels, L. F. A.;Richard, Stephane;Kahnoski, Richard J.;Anema, John;Tuveson, David A.;Perez-Mancera, Pedro A.;Mustonen, Ville;Fischer, Andrej;Adams, David J.;Rust, Alistair;Chan-on, Waraporn;Subimerb, Chutima;Dykema, Karl;Furge, Kyle;Campbell, Peter J.;Teh, Bin Tean;Stratton, Michael R.;Futreal, P. Andrew
通讯作者：
Futreal, P. Andrew
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：
64.8
作者：
Bellaiche, Y;The, I;Perrimon, N
通讯作者：
Perrimon, N
影响因子：
4.8
作者：
Takada, T;Katagiri, T;Kamijo, R
通讯作者：
Kamijo, R