Abstract
Human chorionic gonadotrophin (hCG) is released from placental trophoblasts and is involved in establishing pregnancy by maintaining progesterone secretion from the corpus luteum. Serum hCG is detected in the maternal circulation within the first 2–3 wks of gestation and peaks at the end of the first trimester before declining. In Down's syndrome (DS) pregnancies, serum hCG remains significantly high compared to gestation age-matched uncompromised pregnancies. It has been proposed that increased serum hCG levels could be due to transcriptional hyper-activation of the CGB (hCG beta) gene, or an increased half life of glycosylated hCG hormone, or both. Another possibility is that serum hCG levels remain high due to reduced availability of the hormone's cognate receptor, LHCGR, leading to lack of hormone utilization. We have tested this hypothesis by quantifying the expression of the hCG beta (CGB) RNA, LHCGR RNA and LHCGR proteins in chorionic villous samples. We demonstrate that chorionic expression of hCG beta (CGB) mRNA directly correlates with high serum hCG levels. The steady-state synthesis of LHCGR mRNA (exons 1–5) in DS pregnancies was significantly higher than that of controls, but the expression of full-length LHCGR mRNA (exons 1–11) in DS was comparable to that of uncompromised pregnancies. However, the synthesis of high molecular weight mature LHCGR proteins was significantly reduced in DS compared to uncompromised pregnancies, suggesting a lack of utilization of circulating hCG in DS pregnancies.
Highlights
The incidence of aneuploidy in human pregnancies is unusually high (1–2%) compared to other mammals [1]
The goal of this study was to examine the placental expression of the LH/hCG receptor (LHCGR) mRNA and functional receptor protein expression with respect to serum Human chorionic gonadotrophin (hCG) concentrations in Down's syndrome pregnancies
chorionic expression of hCG beta (CGB) and LHCGR genes are hyperactivated in Down's syndrome pregnancies The hCG α subunit is synthesized in excess and is common to all members of this hormone family, whereas the hCG β subunit, which recognizes the cognate receptor, is specific for the hormone
Summary
The incidence of aneuploidy in human pregnancies is unusually high (1–2%) compared to other mammals [1]. Monosomies and trisomies together account for 35% of clinically detected spontaneous abortions (6–20 wks of gestation), stillbirth (4%) and most importantly, are the leading cause of developmental disability and mental retardation of those surviving such pregnancies [2,3,4]. Of all the genetically compromised pregnancies, Down's syndrome (Trisomy 21, T21) is the most frequent (1/700 live births [5]). The Edward's (Trisomy 18, T18) and Pautau's (Trisomy 13, T13) syndromes are considered relatively rare pregnancy disorders with a prevalence at birth of 1 in 7000 and 29000, respectively [6,7]. 89–95% of Down's syndrome (DS) patients carry an extra chromosome 21 (chr 21) which arises due to meiotic nondysjunction and is usually inherited from the mother [1]. In addition to the characteristic variability in mental retardation, physical and facial features, congenital heart and gastro-intestinal defects, the DS patients are susceptible to leukaemia and Alzheimer's-like dementia [9,10,11]
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