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-dimer (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 assays 1 and 2 is 1.18-2.10 (range of mean +/- 2 SD) in wild-type subjects, 0.54-0.98 in heterozygotes, and below 0.15 in homozygotes with regard to the mutant LH beta allele. Analysis of sera from 249 healthy male and female subjects of Finnish origin revealed a frequency of 24.1% heterozygotes and 3.6% homozygotes for the mutation, with similar proportions in each sex. The ratio of in vitro bioactivity to immunoreactivity (assay 2) of the variant LH was significantly (P < 0.01) increased (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 male and three female subjects homozygous for the LH variant and three matched male and three female controls with wild-type LH. Likewise, the responses of LH immunoreactivity (assay 2) to GnRH stimulation were similar with both types of LH. The half-time of the variant LH in rat circulation from both sexes was significantly shorter than that of LH from control subjects (males, 25.5 +/- 3.8 vs. 48.3 +/- 2.7 min, respectively; P < 0.01; n = 3). Upon isoelectric focusing of peripheral serum samples, the isoform distribution of the variant LH was similar to that of wild-type LH. In conclusion, the LH variant discovered by us appears to occur with high frequency in the Finnish population (28% homo- or heterozygotes). It has increased in vitro bioactivity and a decreased half-time in vivo. These differences are compatible with a putative extra carbohydrate chain in the LH beta-chain, as one of the two mutations introduces an extra glycosylation signal. The subjects homozygous for the LH polymorphism are apparently healthy. However, the altered 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.
Haavisto
A M
AM
Department of Physiology, University of Turku, Finland.
Pettersson
K
K
Bergendahl
M
M
Virkamäki
A
A
Huhtaniemi
I
I
D000328:Adult; D000368:Aged; D005260:Female; D005387:Finland; D005787:Gene Frequency; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007536:Isomerism; D007986:Luteinizing Hormone / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D012016:Reference Values
D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone