Imperial College London
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ProfessorLesleyRegan

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Clinical Professor
 
 
 
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Contact

 

+44 (0)20 3312 1798l.regan

 
 
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Assistant

 

Ms Hazel Blackman +44 (0)20 7594 2104

 
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Location

 

MWG022Mint WingSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Demetriou:2019:hmg/ddz203,
author = {Demetriou, C and Chanudet, E and GOSgene and Joseph, A and Topf, M and Thomas, AC and Bitner-Glindzicz, M and Regan, L and Stanier, P and Moore, GE},
doi = {hmg/ddz203},
journal = {Human Molecular Genetics},
pages = {3466--3474},
title = {Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans},
url = {http://dx.doi.org/10.1093/hmg/ddz203},
volume = {28},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Demetriou,C
AU  - Chanudet,E
AU  - GOSgene
AU  - Joseph,A
AU  - Topf,M
AU  - Thomas,AC
AU  - Bitner-Glindzicz,M
AU  - Regan,L
AU  - Stanier,P
AU  - Moore,GE
DO  - hmg/ddz203
EP  - 3474
PY  - 2019///
SN  - 0964-6906
SP  - 3466
TI  - Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans
T2  - Human Molecular Genetics
UR  - http://dx.doi.org/10.1093/hmg/ddz203
UR  - https://www.ncbi.nlm.nih.gov/pubmed/31504499
UR  - https://academic.oup.com/hmg/article/28/20/3466/5552779
UR  - http://hdl.handle.net/10044/1/73586
VL  - 28
ER  -
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