The objective of the study is the functional characterization of a novel POU1F1 c.605delC mutation in combined pituitary hormone deficiency (CPHD) and to report the clinical and genetic details of 160 growth hormone deficiency patients. Screening of GH1, GHRHR, POU1F1, PROP1, and HESX1 genes by Sanger sequencing was carried out in 160 trios and 100 controls followed by characterization of the POU1F1 c.605delC mutation by expression studies including site directed mutagenesis, co-transfection, protein degradation, and luciferase assays to compare the wild type and mutant POU1F1. In vitro studies showed that the POU1F1 c.605delC mutation codes for a truncated protein with reduced transactivation capacity on its downstream effectors, viz., growth hormone (GH) and prolactin (PRL) causing severe CPHD. Experiments using different protease inhibitors reveal rescue of the protein upon blockage of the lysosomal pathway that might be useful in novel drug designing using targeted approach thereby maintaining the milieu and preventing/delaying the disease. The study provides an insight into the disease causing mechanism of POU1F1 c.605delC mutation identified in a CPHD child with severe short stature and failure to thrive. It also shows mutation effect on the expression, function and turnover of protein and highlights mechanistic details by which these potent regulators may operate.
this meeting were the critical evaluation of placental physiology and its development.Special emphasis was placed on understanding the consequences and implications of placental development in sustenance of pregnancy and in pregnancy-associated complications such as preeclampsia, intrauterine growth restriction, and preterm birth.This meeting brought together experienced as well as novice clinicians and biologists who have a keen interest in the field of placental biology, including development of new technologies and methods for evaluating the role of placenta in predicting pregnancy outcomes. The meeting primarily focused on (i) high-throughput "-omics" approaches, (ii) maternal nutrition and placental function, (iii) placental infection and inflammation, (iv) real-time evaluation of placental development: tools for placental research, and (v) epidemiologic relevance of placental-based research. Unanimous consensus emerged among the participants to carry out additional work focused on these areas. In this article, we summarize the talks and review the published literature on the above-mentioned niches. As a direct outcome of this meeting, a request for applications has been announced by the Department of Biotechnology, Government of India, for pursuing research in this vital but understudied domain. K E Y W O R D Sclinical imaging, epidemiology, maternal nutrition, omics, placenta | LAYING THE BACKGROUNDProf. Renu Dhingra, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, introduced the basics of placental anatomy and development. Placenta is a noteworthy organ that has evolved to support fetus in utero and is likely to be the key determinant of fetal growth. Formation of placenta requires a developmental progression, which proceeds in a specific order over time, specified by the trophoblast but dependent on maternal environment for correct expression.The trophoblast of the embedded/implanted blastocyst differentiates into two cellular layers inner mononuclear cytotrophoblast and outer multinucleated syncytiotrophoblast. Development of this discoid, chorioallantoic, and haemochorial human placenta is then characterized by lacunar and villous stages thus giving rise to primary, secondary, and tertiary chorionic villi. The development of placenta is not autonomous but is affected by maternal, periconceptional, genetic, and immune factors, which further influence the process of implantation, spiral artery remodeling, uteroplacental blood flow, and thus placental supply of nutrients and oxygen to fetus. Placental structural and functional abnormalities may not only cause numerous adverse pregnancy outcomes but also affect the long-term health of both mother and offspring. Thus, increasing the understanding of its structure and
Problem Small for gestational age (SGA) neonates are vulnerable to various long and short‐term adverse health consequences. The expression of HLA‐G in the placenta is crucial for establishment and maintenance of pregnancy. Its aberrant expression could lead to perturbed immunological interactions in the placenta which could be associated with SGA births. The objective of this study was to assess the difference in the trajectories of soluble HLA‐G in maternal sera during pregnancy between women delivering SGA and appropriate for gestational age (AGA) neonates. Method of study Soluble HLA‐G was estimated in the maternal sera collected at different time points in pregnancy of North‐Indian pregnant females delivering SGA (N = 23) or AGA (N = 17) neonates using sandwich ELISA. Linear mixed models were built and compared to study the association between sHLA‐G levels during pregnancy and SGA births. Results No significant difference was observed in the sHLA‐G trajectories during pregnancy in mothers delivering SGA as compared to those delivering AGA (P‐value = .5677). A trend towards higher sHLA‐G levels at the first trimester of pregnancy (< 14 weeks of gestation) was observed in mothers delivering SGA neonates (Median = 41.71, IQR = 21.31–71.38) as compared to those delivering AGA neonates (Median = 37.58, IQR = 19.05–73.57). Conclusion During pregnancy, sHLA‐G trajectories do not differ significantly between mothers delivering SGA and those delivering AGA neonates. However, sHLA‐G trends towards higher levels during early pregnancy in mothers delivering SGA neonates.
Preeclampsia is a pregnancy-specific disorder involving placental abnormalities. Elevated placental Sialic acid immunoglobulin-like lectin (Siglec)-6 expression has been correlated with preeclampsia. Siglec-6 is a transmembrane receptor, expressed predominantly by the trophoblast cells in the human placenta. It interacts with sialyl glycans such as sialyl-TN glycans as well as binds leptin. Siglec-6 overexpression has been shown to influence proliferation, apoptosis, and invasion in the trophoblast (BeWo) cell model. However, there is no direct evidence that Siglec-6 plays a role in preeclampsia pathogenesis and its signaling potential is still largely unexplored. Siglec-6 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an ITIM-like motif in its cytoplasmic tail suggesting a signaling function. Site-directed mutagenesis and transfection were employed to create a series of Siglec-6 expressing HTR-8/SVneo trophoblastic cell lines with mutations in specific functional residues to explore the signaling potential of Siglec-6. Co-immunoprecipitation and inhibitory assays were utilized to investigate the association of Src-kinases and SH-2 domain-containing phosphatases with Siglec-6. In this study, we show that Siglec-6 is phosphorylated at ITIM and ITIM-like domains by Src family kinases. Phosphorylation of both ITIM and ITIM-like motifs is essential for the recruitment of phosphatases like Src homology region 2 containing protein tyrosine phosphatase 2 (SHP-2), which has downstream signaling capabilities. These findings suggest Siglec-6 as a signaling molecule in human trophoblasts. Further investigation is warranted to determine which signaling pathways are activated downstream to SHP-2 recruitment and how overexpression of Siglec-6 in preeclamptic placentas impacts pathogenesis.
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