Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma.
Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma.
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DOI：
10.1084/jem.20101597
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发表时间：
2010-10-25
期刊：
影响因子：
--
通讯作者：
Casanova JL
中科院分区：
文献类型：
--
作者：
Byun M;Abhyankar A;Lelarge V;Plancoulaine S;Palanduz A;Telhan L;Boisson B;Picard C;Dewell S;Zhao C;Jouanguy E;Feske S;Abel L;Casanova JL
全外显子组测序显示，在一个典型的卡波西肉瘤的儿童中，编码STIM1的基因发生了纯合子剪接点突变。经典卡波西肉瘤(KS)在地中海盆地的儿童中非常罕见，尽管该地区人类疱疹病毒-8(HHV-8)感染的发病率很高。我们推测，对HHV-8免疫的罕见单基因先天错误可能是儿童时期典型KS的基础。我们调查了一名没有其他异常严重的感染或肿瘤表型的儿童，他在两岁时死于播散性KS。患者的整个外显子组测序显示，STIM1基因存在纯合子剪接点突变，STIM1是一种编码基质相互作用分子1的基因，它调节存储操作的钙离子进入。在患者的EB病毒转化的B细胞系中，STIM1的mRNA剪接、蛋白质产生和钙离子内流完全被取消，但通过野生型STIM1的表达而被拯救。根据先前在单个严重T细胞免疫缺陷家庭中发现的STIM1缺陷，以及获得性T细胞缺陷个体发生KS的风险更高，我们得出结论，STIM1 T细胞缺陷导致该儿童感染HHV-8后发生致死性KS。我们的报告首次提供了儿童时期孤立的经典KS可能由单基因缺陷引起的证据，并提供了原理证明，即单个患者的整个外显子组测序可以破译罕见先天性错误的遗传基础。
Whole-exome sequencing reveals a homozygous splice-site mutation in the gene encoding STIM1 in a child with classic Kaposi sarcoma. Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca2+ entry. STIM1 mRNA splicing, protein production, and Ca2+ influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.
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DOI：
10.1002/mpo.10078
发表时间：
2002-08-01
期刊：
MEDICAL AND PEDIATRIC ONCOLOGY
影响因子：
--
作者：
Ferrari, A;Casanova, M;Carli, M
通讯作者：
Carli, M
影响因子：
8.7
作者：
通讯作者：
--
影响因子：
5.1
作者：
Camcioglu, Y;Picard, C;Casanova, JL
通讯作者：
Casanova, JL
影响因子：
30.8
作者：
Hoischen, Alexander;van Bon, Bregje W. M.;Veltman, Joris A.
通讯作者：
Veltman, Joris A.
影响因子：
3.9
作者：
Lalonde, Emilie;Albrecht, Steffen;Jabado, Nada
通讯作者：
Jabado, Nada