Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male-limited precocious puberty.
Genomic DNA from 32 unrelated families with male-limited precocious puberty was examined for the previously described Asp-578-->Gly, Met-571-->Ile, and Thr-577-->Ile mutations in transmembrane helix 6 of the human luteinizing hormone receptor (hLHR). Twenty-eight families had the inherited form of the disorder, and of these, 24 were found to have the Asp-578-->Gly mutation. Four additional mutations were found among the remaining four families with the inherited form and in four sporadic cases of the disorder: an A-->C transversion resulting in substitution of leucine for Ile-542 in the fifth transmembrane helix, an A-->G transition resulting in substitution of glycine for Asp-564 in the third cytoplasmic loop, a G-->T transversion resulting in substitution of tyrosine for Asp-578 in the sixth transmembrane helix, and a T-->C transition resulting in substitution of arginine for Cys-581 in the sixth transmembrane helix. Human embryonic kidney cells transfected with cDNAs for each of the mutant hLHRs, created by PCR-based mutagenesis of the wild-type hLHR cDNA, exhibited increased levels of basal cAMP production in the absence of agonist, indicating constitutive activation of the mutation hLHRs. Three of the additional mutations had specific features: Ile-542-->Leu and Cys-581-->Arg appeared ligand-unresponsive, whereas Asp-578-->Tyr appeared to correlate genotype with phenotype. We conclude that the region spanning nt 1624-1741 of exon 11 is a hotspot for heterogeneous point mutations that constitutively activate the hLHR and cause male-limited precocious puberty.
Laue
L
L
Department of Pediatrics, Georgetown University Medical Center, Washington, D.C. 20007.
Chan
W Y
WY
Hsueh
A J
AJ
Kudo
M
M
Hsu
S Y
SY
Wu
S M
SM
Blomberg
L
L
Cutler
G B
GB
D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid; D001483:Base Sequence; D002460:Cell Line; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D018076:DNA, Complementary; D005998:Glycine; D015186:Hominidae / Q000235:genetics*; D006801:Humans; D007532:Isoleucine; D007930:Leucine; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D017433:Protein Structure, Secondary; D011629:Puberty, Precocious / Q000235:genetics*; D011974:Receptors, LH / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D015183:Restriction Mapping; D015398:Signal Transduction; D014162:Transfection
D006063:Chorionic Gonadotropin; D017931:DNA Primers; D018076:DNA, Complementary; D011974:Receptors, LH; D011994:Recombinant Proteins; D007532:Isoleucine; D001224:Aspartic Acid; D004247:DNA; D000242:Cyclic AMP; D007930:Leucine; D005998:Glycine