Genetic heterogeneity of constitutively activating mutations of the human luteinizing hormone receptor in familial male-limited precocious puberty.

• DOI: 10.1073/pnas.92.6.1906
• Publication Date: 2006-05-31T13:29:22Z
• Authors: L Laue; W Y Chan; A J Hsueh; M Kudo; S Y Hsu; S M Wu; L Blomberg; G B Cutler
• Keywords: Transversion

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 human luteinizing hormone receptor (hLHR). Twenty-eight had inherited form disorder, these, 24 were found to have Asp-578-->Gly mutation. Four additional among remaining four sporadic cases disorder: an A-->C transversion resulting substitution leucine Ile-542 fifth helix, A-->G transition glycine Asp-564 third cytoplasmic loop, a G-->T tyrosine Asp-578 sixth T-->C arginine Cys-581 helix. Human embryonic kidney cells transfected cDNAs each mutant hLHRs, created by PCR-based mutagenesis wild-type hLHR cDNA, exhibited increased levels basal cAMP production absence agonist, indicating constitutive activation mutation hLHRs. Three specific features: Ile-542-->Leu Cys-581-->Arg appeared ligand-unresponsive, whereas Asp-578-->Tyr correlate genotype phenotype. We conclude that region spanning nt 1624-1741 exon 11 is hotspot heterogeneous point constitutively activate cause puberty.