Genetic and epigenetic factors at COL2A1 and ABCA4 influence clinical outcome in congenital toxoplasmosis.
Genetic and epigenetic factors at COL2A1 and ABCA4 influence clinical outcome in congenital toxoplasmosis.
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COL2A1和ABCA4的遗传和表观遗传因子会影响先天性弓形虫病的临床结果。
DOI：
10.1371/journal.pone.0002285
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发表时间：
2008-06-04
期刊：
影响因子：
3.7
通讯作者：
Blackwell, Jenefer M.
中科院分区：
文献类型：
--
作者：
Jamieson, Sarra E.;de Roubaix, Lee-Anne;Cortina-Borja, Mario;Tan, Hooi Kuan;Mui, Ernest J.;Cordell, Heather J.;Kirisits, Michael J.;Miller, E. Nancy;Peacock, Christopher S.;Hargrave, Aubrey C.;Coyne, Jessica J.;Boyer, Kenneth;Bessieres, Marie-Helene;Buffolano, Wilma;Ferret, Nicole;Franck, Jacqueline;Kieffer, Francois;Meier, Paul;Nowakowska, Dorota E.;Paul, Malgorzata;Peyron, Francois;Stray-Pedersen, Babill;Prusa, Andrea-Romana;Thulliez, Philippe;Wallon, Martine;Petersen, Eskild;McLeod, Rima;Gilbert, Ruth E.;Blackwell, Jenefer M.
妊娠期原发性弓形虫感染可传染给胎儿。出生时，感染的婴儿可能有颅内钙化、脑积水和视网膜脉络膜炎，出生后任何年龄都可能出现新的眼部病变。并非所有在子宫内感染的儿童都会出现这些疾病的临床症状。虽然疾病的严重程度受到母亲感染的三个月的影响，但包括遗传易感性在内的其他因素也可能有所贡献。在来自欧洲的457对母子和来自北美的149对儿童/父母三人组中，我们发现先天性弓形虫病的眼部和脑部疾病与ABCA 4编码ATP结合盒转运蛋白亚家族A成员4的多态性相关。编码II型胶原的COL 2A 1的多态性仅与眼部疾病相关。两个基因座显示不寻常的遗传模式的疾病等位基因时，在杂合子受影响的儿童与杂合子母亲的受影响的儿童的结果进行比较。建模建议要么母亲的基因型的影响，或父母的原产地的影响。实验研究表明，ABCA 4和COL 2A 1都显示出与印迹一致的异构体特异性表观遗传修饰。先天性弓形虫病的临床结局与ABCA 4和COL 2A 1多态性之间的这些关联为了解可能受该寄生虫先天性感染影响的分子途径提供了新的见解。
Primary Toxoplasma gondii infection during pregnancy can be transmitted to the fetus. At birth, infected infants may have intracranial calcification, hydrocephalus, and retinochoroiditis, and new ocular lesions can occur at any age after birth. Not all children who acquire infection in utero develop these clinical signs of disease. Whilst severity of disease is influenced by trimester in which infection is acquired by the mother, other factors including genetic predisposition may contribute. In 457 mother-child pairs from Europe, and 149 child/parent trios from North America, we show that ocular and brain disease in congenital toxoplasmosis associate with polymorphisms in ABCA4 encoding ATP-binding cassette transporter, subfamily A, member 4. Polymorphisms at COL2A1 encoding type II collagen associate only with ocular disease. Both loci showed unusual inheritance patterns for the disease allele when comparing outcomes in heterozygous affected children with outcomes in affected children of heterozygous mothers. Modeling suggested either an effect of mother's genotype, or parent-of-origin effects. Experimental studies showed that both ABCA4 and COL2A1 show isoform-specific epigenetic modifications consistent with imprinting. These associations between clinical outcomes of congenital toxoplasmosis and polymorphisms at ABCA4 and COL2A1 provide novel insight into the molecular pathways that can be affected by congenital infection with this parasite.
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