A 3.7 Mb deletion encompassing ZEB2 causes a novel polled and multisystemic syndrome in the progeny of a somatic mosaic bull.
A 3.7 Mb deletion encompassing ZEB2 causes a novel polled and multisystemic syndrome in the progeny of a somatic mosaic bull.
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DOI：
10.1371/journal.pone.0049084
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Pailhoux E
中科院分区：
文献类型：
--
作者：
Capitan A;Allais-Bonnet A;Pinton A;Marquant-Le Guienne B;Le Bourhis D;Grohs C;Bouet S;Clément L;Salas-Cortes L;Venot E;Chaffaux S;Weiss B;Delpeuch A;Noé G;Rossignol MN;Barbey S;Dozias D;Cobo E;Barasc H;Auguste A;Pannetier M;Deloche MC;Lhuilier E;Bouchez O;Esquerré D;Salin G;Klopp C;Donnadieu C;Chantry-Darmon C;Hayes H;Gallard Y;Ponsart C;Boichard D;Pailhoux E
无角多系统综合征（Polled and Multisystemic Syndrome，PMS）是一种发生于单头公牛后代的新型发育障碍性疾病，其临床表现包括无角（角完全不发育）、面部畸形、生长迟缓、慢性腹泻、卵巢早衰以及各种神经和心脏异常。经前综合征的特征还在于性别比例的偏离，这表明男性在怀孕期间死亡。使用孟德尔错误定位和全基因组测序，我们确定了一个3.7 Mb的缺失在父系牛2号染色体上，包括ARHGAP 15，GTDC 1和ZEB 2基因。然后我们制作了对照组并影响了90天大的胎儿，通过组织学和表达分析来描述这种综合征的特征。与野生型个体相比，受影响的动物显示出三个缺失基因的表达降低。基于与人类Mowat-Wilson综合征的比较，我们认为ZEB 2的缺失是该突变的大部分效应的原因。最后，精子FISH，胚胎基因分型和生殖记录的分析证实了体细胞嵌合体的创始人公牛和男性特定的死亡率在前三分之一的妊娠。总之，我们确定了一个新的位点参与牛角个体发育，并建议上皮细胞间充质转化角芽分化中起着至关重要的作用。我们还提供了新的见解ZEB 2杂合性丢失在牛和人类的致病性，并描述了第一例与非鼠哺乳动物物种中的常染色体基因座相关的男性特异性致死性。这一结果使PMS成为研究性别特异性基因表达/调控的独特模型。
Polled and Multisystemic Syndrome (PMS) is a novel developmental disorder occurring in the progeny of a single bull. Its clinical spectrum includes polledness (complete agenesis of horns), facial dysmorphism, growth delay, chronic diarrhea, premature ovarian failure, and variable neurological and cardiac anomalies. PMS is also characterized by a deviation of the sex-ratio, suggesting male lethality during pregnancy. Using Mendelian error mapping and whole-genome sequencing, we identified a 3.7 Mb deletion on the paternal bovine chromosome 2 encompassing ARHGAP15, GTDC1 and ZEB2 genes. We then produced control and affected 90-day old fetuses to characterize this syndrome by histological and expression analyses. Compared to wild type individuals, affected animals showed a decreased expression of the three deleted genes. Based on a comparison with human Mowat-Wilson syndrome, we suggest that deletion of ZEB2, is responsible for most of the effects of the mutation. Finally sperm-FISH, embryo genotyping and analysis of reproduction records confirmed somatic mosaicism in the founder bull and male-specific lethality during the first third of gestation. In conclusion, we identified a novel locus involved in bovid horn ontogenesis and suggest that epithelial-to-mesenchymal transition plays a critical role in horn bud differentiation. We also provide new insights into the pathogenicity of ZEB2 loss of heterozygosity in bovine and humans and describe the first case of male-specific lethality associated with an autosomal locus in a non-murine mammalian species. This result sets PMS as a unique model to study sex-specific gene expression/regulation.
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影响因子：
1.9
作者：
Leong, May;Verey, Frances;Ramani, Pramila
通讯作者：
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影响因子：
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