Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans
File(s)D-00429 Demetriou submitted.pdf (662.84 KB)
Accepted version
Author(s)
Type
Journal Article
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 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.
Date Issued
2019-10-15
Date Acceptance
2019-08-12
Citation
Human Molecular Genetics, 2019, 28 (20), pp.3466-3474
ISSN
0964-6906
Publisher
Oxford University Press (OUP)
Start Page
3466
End Page
3474
Journal / Book Title
Human Molecular Genetics
Volume
28
Issue
20
Copyright Statement
© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This is a pre-copy-editing, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version Charalambos Demetriou, Estelle Chanudet, GOSgene, Agnel Joseph, Maya Topf, Anna C Thomas, Maria Bitner-Glindzicz, Lesley Regan, Philip Stanier, Gudrun E Moore, Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans, Human Molecular Genetics, Volume 28, Issue 20, 15 October 2019, Pages 3466–3474 is available online at: https://doi.org/10.1093/hmg/ddz203
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31504499
PII: 5552779
Subjects
GOSgene
06 Biological Sciences
11 Medical and Health Sciences
Genetics & Heredity
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2019-08-22