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    Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans

    Demetriou, C. and Chanudet, E. and Joseph, Agnel and Topf, Maya and Thomas, A.C. and Bitner-Glindzicz, M. and Regan, L. and Stanier, P. and Moore, G.E. (2019) Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans. Human Molecular Genetics 28 (20), pp. 3466-3474. ISSN 0964-6906.

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    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 domains reported to be involved in Hsp90 binding and peptidyl-prolyl cic-trans isomerase (PPIase) activity. Profound effects on PPIase activity were demonstrated in transiently transfected HEK293 cells comparing wildtype 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. [Abstract copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email:]


    Item Type: Article
    Keyword(s) / Subject(s): pregnancy, abortion, habitual abortion, spontaneous fetal death, hsp90 heat-shock proteins, infertility, isomerase, marriage, life event, peptidylprolyl isomerase, tacrolimus binding proteins, genetics, mice, proband, candidate disease gene, asian, hek293 cells, whole exome sequencing
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    SWORD Depositor: Mr Joe Tenant
    Depositing User: Mr Joe Tenant
    Date Deposited: 09 Oct 2019 09:40
    Last Modified: 02 Aug 2023 17:54


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