Human Molecular Genetics, Vol 8, 2037-2046, Copyright © 1999 by Oxford University Press
M Jiang, P Pakarinen, FP Zhang, T El-Hefnawy, P Koskimies, K Pettersson and I Huhtaniemi
A common genetic variant (V) of the human luteinizing hormone (LH) beta-
subunit gene was recently discovered. The V-LH molecules have higher
bioactivity in vitro, but shorter half-life in circulation, which
apparently is related to the alterations of LH function observed in
individuals homo- and heterozygous for the V-LHbeta allele. We have now
studied whether additional mutations in the V-LHbeta promoter sequence
could contribute to the altered physiology of the LH variant molecules. The
661 bp 5'-flanking region of the V-LHbeta gene, retrieved from human
genomic DNA by PCR, contained eight single-nucleotide changes, as compared
with the wild-type (wt) LHbeta promoter. The finding was consistent in DNA
samples of different ethnic groups. Reporter constructs with various
lengths of the wt- and V-LH promoter sequences, driving the firefly
luciferase reporter gene, were transfected into an immortalized mouse
pituitary cell line, LbetaT(2), known to express the endogenous LHbeta
gene, and into a non-endocrine human embryonic kidney cell line, HEK 293.
Basal expression levels of the V-LHbeta promoter constructs were on average
36% higher in LbetaT(2)cells ( P < 0.001; n = 29), and 40% higher in HEK
293 cells ( P < 0.001; n = 16), as compared with the respective wt
sequences. Numerous qualitative and quantitative differences were found
between the two cell lines in responses of the two promoter sequences to
stimulation with 12- O - tetradecanoylphorbol-13-acetate, forskolin,
8-bromo-cAMP, progesterone and gonado- tropin-releasing hormone. In
conclusion, the V-LHbeta promoter has higher basal activity, and differs in
response to hormonal stimulation, as compared with the wt-LHbeta promoter.
The altered promoter function of the V-LHbeta gene provides evidence for
differences in regulation of the wt- and V-LHbeta genes, which may
contribute to the differences observed in pituitary-gonadal function
between carriers of the two LHbeta alleles. The findings also suggest a
novel evolutionary mechanism whereby polymorphic changes resulting in
altered bioactivity of a gene product may be compensated for by additional
mutations in the cognate promoter sequence, changing transcription of the
same gene.
ARTICLES
A common polymorphic allele of the human luteinizing hormone beta- subunit gene: additional mutations and differential function of the promoter sequence
Department of Physiology and.
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