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

Demetriou, C; Chanudet, E; GOSgene, .; Joseph, A; Topf, M; Thomas, AC; Bitner-Glindzicz, M; ... Moore, GE; + view all (2019) Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans. Human Molecular Genetics , 28 (20) pp. 3466-3474. 10.1093/hmg/ddz203. Green open access

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Abstract

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.

Type: Article
Title: Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddz203
Publisher version: https://doi.org/10.1093/hmg/ddz203
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: pregnancyabortion, habitualabortion, spontaneousfetal deathhsp90 heat-shock proteinsinfertilityisomerasemarriage, life event, peptidylprolyl isomerase, tacrolimus binding proteins, genetics, mice, proband, candidate disease gene, asian, fkbp5 gene, hek293 cells, whole exome sequencing
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10079840
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