The LH receptor is a member of the large receptor family of GTP-binding protein coupled receptors. Mutations in the LH receptor gene cause severe sex hormone-related disease, ranging from very early precocious puberty in boys (activating mutation) to slight undervirilization, severe hypospadias or complete 46XY pseudohermaphroditism (inactivating mutation). Thus, LH receptor gene mutations have profound effects on sex hormone production and on physiology of patients. In addition, the strength of the phenotype follows the in vitro activity of the various LH receptor mutant proteins. Thus the question has arisen whether slight changes in LH receptor activity, such as caused by polymorphic gene variants, may have subtle effects on susceptibility, disease progression or response to treatment of sex hormone-dependent disease. The most frequent LH receptor polymorphisms that involve an amino acid change are the absence or presence of a two amino acid (LQ) insertion at position 18 in exon 1 (rs4539842) and two variable amino acids at position 291 and 312 respectively: 291Asn/Ser (rs12470652) and 312Ser/Asn (rs2293275). The latter are of interest because of their location in exon 10, which is involved in the differential sensitivity of the LH receptor to LH and hCG. The 291Asn/Ser and 312Ser/Asn SNPs are located at or near glycosylation sites, respectively. The polymorphic LQ insertion is located in the signal peptide, which enables translocation of the LH receptor into the endoplasmic reticulum where protein maturation processes are carried out. The LQ insertion had a clear effect on in vitro LH receptor expression and showed an association with worse disease free survival in breast cancer patients. Although we could not detect a functional effect of the 312SN polymorphism, this allele appears to be a weak risk allele for breast cancer. The 291S LH receptor variant is more sensitive to LH in vitro, but its low frequency did not allow association studies in our breast cancer cohort.
25 - 29 Apr 2009
European Society of Endocrinology