A common genetic variant of luteinizing hormone; relation to normal and aberrant pituitary-gonadal function.

Mutations of the luteinizing hormone (LH) subunit genes are extremely rare. Only one polymorphic LHbeta gene variant makes an exception. In 1992, an immunologically anomalous form of LH was found in a healthy woman, and it was subsequently found to be caused by two point mutations leading to two amino acid substitutions in the LHbeta subunit. Of the two point mutations, Trp(8)Arg and Ile(15)Thr, the first one is mainly responsible for the altered immunoreactivity and the latter one introduces an extra glycosylation site into Asn(13) of the mutated LHbeta peptide. The frequency of this variant LHbeta allele differs widely between ethnic groups, being most common in aboriginal Australians (carrier frequency >50%; allelic frequency 28.3%) and totally lacking from Kotas of Southern India. Functional differences have been detected when wild-type LH and variant LH have been compared. Variant LH possesses increased in vitro bioactivity, whereas its half-life in circulation is shorter in comparison to wild-type LH. Also the regulation of the variant LHbeta gene differs due to additional changes in its promoter sequence. Correlations of occurrence of variant LH with various clinical conditions involving LH function suggest that it represents a biologically less active form of LH and may be related to borderline suppression of gonadal function, including subfertility. In this article, we will review the current information about the differences observed in structure and functions between the wild-type and variant LH, as well as their possible pathophysiological correlations.