Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction

Abstract

The FSH receptor shows three single nucleotide polymorphisms (SNPs), one in the promoter and two in exon 10. In addition, the FSH receptor mRNA undergoes extensive alternative splicing. While no physiological role for the SNP in the promoter and for alternative spliced isoforms has been demonstrated so far, the SNPs in exon 10 result in four discrete allelic variants characterized by the amino acid combinations Thr307-Asn680, Ala307-Ser680, Ala307-Asn680 and Thr307-Ser680. Several studies have demonstrated that the first two allelic variants are very frequent (approximately 60 and 40% respectively) in the Caucasian population. The rarer Ala307-Asn680 and Thr307-Ser680 variants are much less frequent (<5%) in the Chinese. In males the FSH receptor variants are not related to testicular volume, serum FSH or serum inhibin B levels. The two most common receptor variants transiently transfected in COS-7 cells displayed similar functional characteristics. Frequency distribution of the two polymorphisms in normal women and patients with polycystic ovarian syndrome or premature ovarian failure is still under investigation. The homozygous Ala307-Ser680 variant seems to be associated with significantly higher basal serum FSH levels and with a higher amount of FSH required for ovarian stimulation in women undergoing assisted reproduction. This suggests that the FSH receptor genotype can influence the ovarian response to FSH stimulation. The presence of SNPs in the FSH receptor gene capable of modifying FSH action paves the way for future patient-tailored, genotype-based hormone therapies.

FSH-receptor Ala307Thr polymorphism is associated to polycystic ovary syndrome and to a higher responsiveness to exogenous FSH in Italian women

“…In the receptor protein, position 307 may be occupied by either Ala or Thr, and position 680 by either Asn or Ser [1,2]. Most available studies were focused on position 680 [3], whereas polymorphism 307 was rarely considered.…”

“…Most available studies were focused on position 680 [3], whereas polymorphism 307 was rarely considered. Position 307 codifies for an amino-acid located within the extracellular domain in the FSHbinding region of the protein [1]: it can affect the hormone-binding ability of the receptor and is crucial for FSH-mediated signal transduction events [15].…”

“…Several polymorphisms of the FSH-R gene have been described; those that involve nucleotides codifying for amino-acids at positions 307 and 680 are the most clinically relevant [1,2]. The relationship between allelic variants at these positions, the presence of polycystic ovary syndrome (PCOS), and the responsiveness to exogenous FSH have been studied in some ethnic groups [3].…”

LH receptor gene expression in cumulus cells in women entering an ART program

“…Thus, genetic studies focus on genes or gene products (molecular biomarkers) that might serve in the assessment of patient's fertility treatment prognosis in order to personalize the treatment accordingly. These studies rely on the identification and characterization of natural variants or polymorphisms in DNA sequence among individuals [23,35].…”

Single nucleotide polymorphisms in the Anti-Müllerian hormone (AMH Ile49Ser) and Anti-Müllerian hormone type II receptor (AMHRII −482 A>G) as genetic markers in assisted reproduction technology

“…Studies have shown that differences seen between individuals or subpopulations of patients are often due to genetic variations, known as single nucleotide polymorphisms (SNPs) in coding regions responsible for the synthesis of hormone receptors, metabolic enzymes or transport molecules, which are specific targets for pharmaceutical drugs. The most studied SNP associated with ovarian response to COS, is the follicle stimulation hormone receptor (FSHR) variant (Ans 680 Ser), which along with estrogen receptor alpha variant (ESR1 gene, Pvull T/C) are practically the only genetic markers applied in clinical tests [4][5][6][7].…”