RESUMEN
BACKGROUND: Human reproductive disorders consist of frequently occurring dysfunctions including a broad range of phenotypes affecting fertility and women's health during pregnancy. Several female-related diseases have been associated with hypofertility/infertility phenotypes, such as recurrent pregnancy loss (RPL). Other occurring diseases may be life-threatening for the mother and foetus, such as preeclampsia (PE) and intra-uterine growth restriction (IUGR). FOXD1 was defined as a major molecule involved in embryo implantation in mice and humans by regulating endometrial/placental genes. FOXD1 mutations in human species have been functionally linked to RPL's origin. METHODS: FOXD1 gene mutation screening, in 158 patients affected by PE, IUGR, RPL and repeated implantation failure (RIF), by direct sequencing and bioinformatics analysis. Plasmid constructs including FOXD1 mutations were used to perform in vitro gene reporter assays. RESULTS: Nine non-synonymous sequence variants were identified. Functional experiments revealed that p.His267Tyr and p.Arg57del led to disturbances of promoter transcriptional activity (C3 and PlGF genes). The FOXD1 p.Ala356Gly and p.Ile364Met deleterious mutations (previously found in RPL patients) have been identified in the present work in women suffering PE and IUGR. CONCLUSIONS: Our results argue in favour of FOXD1 mutations' central role in RPL, RIF, IUGR and PE pathogenesis via C3 and PlGF regulation and they describe, for the first time, a functional link between FOXD1 and implantation/placental diseases. FOXD1 could therefore be used in clinical environments as a molecular biomarker for these diseases in the near future.
Asunto(s)
Aborto Habitual/genética , Retardo del Crecimiento Fetal/genética , Factores de Transcripción Forkhead/genética , Predisposición Genética a la Enfermedad/genética , Preeclampsia/genética , Estudios de Cohortes , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Embarazo , Regiones Promotoras Genéticas/genéticaRESUMEN
Transcription factors (TFs) participate in a wide range of cellular processes due to their inherent function as essential regulatory proteins. Their dysfunction has been linked to numerous human diseases. The forkhead box (FOX) family of TFs belongs to the "winged helix" superfamily, consisting of proteins sharing a related winged helix-turn-helix DNA-binding motif. FOX genes have been extensively present during vertebrates and invertebrates' evolution, participating in numerous molecular cascades and biological functions, such as embryonic development and organogenesis, cell cycle regulation, metabolism control, stem cell niche maintenance, signal transduction, and many others. FOXD1, a forkhead TF, has been related to different key biological processes such as kidney and retina development and embryo implantation. FOXD1 dysfunction has been linked to different pathologies, thereby constituting a diagnostic biomarker and a promising target for future therapies. This paper aims to present, for the first time, a comprehensive review of FOXD1's role in mouse development and human disease. Molecular, structural, and functional aspects of FOXD1 are presented in light of physiological and pathogenic conditions, including its role in human disease aetiology, such as cancer and recurrent pregnancy loss. Taken together, the information given here should enable a better understanding of FOXD1 function for basic science researchers and clinicians.