OCCURRENCE AND BIOLOGICAL PROPERTIES OF A COMMON GENETIC VARIANT OF LUTEINIZING-HORMONE

We have characterized the frequency and selected biological properties of a variant form of LH caused by two point mutations in the gene of the LH beta-subunit. Detection of the LH variant (or polymorphism) is based on aberrant immunoreactivity; it is not detected by a monoclonal antibody (Mab) recognizing a specific epitope in the LH alpha/beta-di mer (assay 1), but an assay using two LH beta-specific Mab recognizes this LH form normally (assay 2). Hence, the ratio of LH measured by as says 1 and 2 is 1.18-2.10 (range of mean +/- 2 SD) in wild-type subjec ts, 0.54-0.98 in heterozygotes, and below 0.15 in homozygotes with reg ard to the mutant LH beta allele. Analysis of sera from 249 healthy ma le and female subjects of Finnish origin revealed a frequency of 24.1% heterozygotes and 3.6% homozygotes for the mutation, with similar pro portions in each sex. The ratio of in vitro bioactivity to immunoreact ivity (assay 2) of the variant LH was significantly (P < 0.01) increas ed (2.9 +/- 0.1; n = 11) compared to that of wild-type LH (2.2 +/- 0.1 ; n = 13). No difference was observed in LH pulsatility, measured from blood samples collected at 5-min intervals for 5 h, between three mal e and three female subjects homozygous for the LH variant and three ma tched male and three female controls with wild-type LH. Likewise, the responses of LH immunoreactivity (assay 2) to GnRH stimulation were si milar with both types of LH. The half-time of the variant LH in rat ci rculation from both sexes was significantly shorter than that of LH fr om control subjects (males, 25.5 +/- 3.8 vs. 48.3 +/- 2.7 min, respect ively; P < 0.01; n = 3). Upon isoelectric focusing of peripheral serum samples, the isoform distribution of the variant LH was similar to th at of wild-type LH. In conclusion, the LH variant discovered by us app ears to occur with high frequency in the Finnish population (28% homo- or heterozygotes). It has increased in vitro bioactivity and a decrea sed half-time in vivo. These differences are compatible with a putativ e extra carbohydrate chain in the LH beta-chain, as one of the two mut ations introduces an extra glycosylation signal. The subjects homozygo us for the LH polymorphism are apparently healthy. However, the altere d bioactivity and in vivo kinetics of the LH variant may induce subtle changes in LH action, either predisposing the affected individuals to or protecting them from disease conditions related to LH action.