The incidence of aneuploidy in human pregnancies is unusually high (1–2%) compared to other mammals . 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 [2–4]. Of all the genetically compromised pregnancies, Down's syndrome (Trisomy 21, T21) is the most frequent (1/700 live births ). 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].
Genetically, 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 . About 1–2% of DS patients have genetic mosaicism (nondysjunction following fertilisation in early embryos), while 3–4% of cases are due to translocation of chr 21 to another autosome, usually chr 14 . In addition to the characteristic variability in mental retardation, physical and facial features, congenital heart and gastro-intestinal defects, the DS patients are also susceptible to leukaemia and Alzheimer's-like dementia [9–11].
The chromosomal abnormalities in DS and other trisomic pregnancies are very often associated with increased or reduced levels of proteins, growth factors and hormones in the maternal blood compared to those of normal pregnancies. For example, in DS pregnancies (11–14 wks of gestation), the serum human chorionic gonadotrophin beta (hCG-β) and pregnancy-associated plasma protein-A (PAPP-A) concentrations tend to be high and low, respectively .
Human chorionic gonadotrophin (hCG) is the key reproductive hormone regulating human pregnancy. It is a member of the family of glycoprotein hormones that includes luteinizing hormone (LH), follicle stimulating and thyroid stimulating hormones, each member of which functions through the formation of a non-covalent heterodimer from two subunits, α and β.
In human placenta hCG is primarily produced by syncytotrophoblasts and to a certain extent by extravillous cytotrophoblasts . One of the earliest endocrine roles of hCG is to sustain the corpus luteum which must produce enough progesterone to establish pregnancy at the outset. In addition, hCG facilitates trophoblast differentiation, remodeling of the uterine epithelium and stroma (decidualization) and endometrium for implantation, invasion of the maternal spiral arterioles, and angiogenesis by acting on vascular smooth muscle and endothelial cells . In normal pregnancies, detectable levels of hCG begin to appear in the maternal circulation at about 2–3 wks after conception, and reach their peak at ~11–13 wks before declining significantly in the later stages of pregnancy. Indeed, high serum hCG levels at mid-late pregnancy have been associated with pre-eclampsia, intra-uterine growth restriction and Down's syndrome (DS) [15–18].
The hCG hormone transduces signals by binding to its specific LH/hCG receptor (LHCGR) expressed on surface of the cell. Since hCG and LH receptors are identical, it is often referred to as the LH/hCG receptor (LHCGR) and is encoded by a single copy ~70 Kb LHCGR gene, located on human chromosome 2p21 . This receptor is structurally very similar to two other hormone receptors (thyroid stimulating and follicle stimulating hormone receptors). The LHCGR gene has 11 exons and codes for multiple alternatively spliced species (at least 6) of mRNA. These different mRNA transcripts are initiated at multiple sites spanning a region more than a kilobase upstream of the first exon .
On the basis of structure and topology, LHCGR is a member of the rhodopsin/β-adrenergic receptor superfamily of G protein-coupled receptors. Agonist (hormone) binding to LHCGR allows dissociation of membrane-bound cognate G proteins that regulate phospholipase C, adenylyl cyclase and ion channels which in turn control cellular inositol phosphates, cAMP, Ca+2 and other secondary messengers [21, 22].
LHCGR is a 701 amino acid residue protein containing three distinct domains: an unusually large (340 residues) N-terminal extracellular domain which binds hCG, a serpentine transmembrane (TM) region containing seven TM repeats connected by three extra- and intracellular loops, and a C-terminal tail. The predicted relative molecular mass (Mr) is ~75 K, or higher, depending upon the level of glycosylation .
Moreover, alternatively spliced mRNAs produce several truncated intra-cellular protein isoforms which have ligand binding capacity but are ineffective in transducing signals . The functional significance of all isoforms remains to be established. However, the accessibility of the Mr 85–95 K species to surface biotinylation, protease and glycosidase (neuraminidase), suggests that they have ligand binding and signal transduction capacities. On the other hand, the Mr 65–75K proteins contain high-mannose type side chains which are susceptible to endoglycosidase H, and are immature and intracellular [25–27]. The high relative molecular mass 165–200K group is thought to be a dimer of the mature functional receptor . Interestingly, smaller species of LHCGR proteins (Mr 45–51K) can be detected in tissues or cells transfected with cDNAs [25–27, 29].
Natural missense  and deletion mutations  of the human LH receptor have been reported to be associated with elevated serum LH levels in these patients. Similarly, the circulating LH concentration remains high [32, 33] in mice carrying a homozygous deletion of Lhr gene (Lhr-/-). Moreover, the lack of functional cytokine receptor expression, due to natural mutations of the IFN-γ receptors 1 and 2, has been directly linked to high serum IFN-γ levels in patients suffering from infectious diseases [34, 35]. These reports prompted us to investigate whether increased serum hCG levels in DS pregnancies could be linked to the expression of its functional receptor in chorionic villi.