Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
Centre for Translational Omics-GOSgene, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
Hum Mol Genet. 2019 Oct 15;28(20):3466-3474. doi: 10.1093/hmg/ddz203.
Recurrent pregnancy loss (RPL) is defined as two or more consecutive miscarriages and affects an estimated 1.5% of couples trying to conceive. RPL has been attributed to genetic, endocrine, immune and thrombophilic disorders, but many cases remain unexplained. We investigated a Bangladeshi family where the proband experienced 29 consecutive pregnancy losses with no successful pregnancies from three different marriages. Whole exome sequencing identified rare genetic variants in several candidate genes. These were further investigated in Asian and white European RPL cohorts, and in Bangladeshi controls. FKBP4, encoding the immunophilin FK506-binding protein 4, was identified as a plausible candidate, with three further novel variants identified in Asian patients. None were found in European patients or controls. In silico structural studies predicted damaging effects of the variants in the structure-function properties of the FKBP52 protein. These were located within domains reported to be involved in Hsp90 binding and peptidyl-prolyl cis-trans isomerase (PPIase) activity. Profound effects on PPIase activity were demonstrated in transiently transfected HEK293 cells comparing wild-type and mutant FKBP4 constructs. Mice lacking FKBP4 have been previously reported as infertile through implantation failure. This study therefore strongly implicates FKBP4 as associated with fetal losses in humans, particularly in the Asian population.
复发性流产（RPL）定义为两次或更多次连续流产，据估计影响了 1.5%的尝试受孕的夫妇。RPL 归因于遗传、内分泌、免疫和血栓形成障碍，但许多病例仍未得到解释。我们调查了一个孟加拉家庭，先证者在三次不同婚姻中经历了 29 次连续妊娠丢失，没有一次成功妊娠。全外显子组测序在几个候选基因中发现了罕见的遗传变异。这些变异在亚洲和白种欧洲 RPL 队列以及孟加拉对照中进一步进行了研究。编码免疫亲和素 FK506 结合蛋白 4 的 FKBP4 被鉴定为一个合理的候选基因，在亚洲患者中又发现了另外三个新的变异。在欧洲患者或对照中均未发现。计算机结构研究预测这些变异会对 FKBP52 蛋白的结构-功能特性产生破坏性影响。这些变异位于报道与 Hsp90 结合和肽脯氨酰顺反异构酶（PPIase）活性有关的结构域内。在瞬时转染的 HEK293 细胞中比较野生型和突变型 FKBP4 构建体，显示出对 PPIase 活性的显著影响。先前已经报道缺乏 FKBP4 的小鼠由于植入失败而不育。因此，这项研究强烈表明 FKBP4 与人类的胎儿丢失有关，特别是在亚洲人群中。
