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Genetic Heterogeneity of Constitutively Activating Mutations of the Human Luteinizing Hormone Receptor in Familial Male-Limited Precocious Puberty

Laue, Louisa ; Chan, Wai-Yee ; Aaron J. W. Hsueh ; Kudo, M. ; Hsu, Sheau Yu ; Wu, Shao-Ming ; Blomberg, LeAnn ; Cutler, Gordon B.

Proceedings of the National Academy of Sciences - PNAS, 1995-03, Vol.92 (6), p.1906-1910 [Periódico revisado por pares]

United States: National Academy of Sciences of the United States of America

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Título:
Genetic Heterogeneity of Constitutively Activating Mutations of the Human Luteinizing Hormone Receptor in Familial Male-Limited Precocious Puberty
Autor: Laue, Louisa ; Chan, Wai-Yee ; Aaron J. W. Hsueh ; Kudo, M. ; Hsu, Sheau Yu ; Wu, Shao-Ming ; Blomberg, LeAnn ; Cutler, Gordon B.
Assuntos: Amino Acid Sequence ; Animals ; Aspartic Acid ; Base Sequence ; Cell Line ; Cells ; Chorionic Gonadotropin - pharmacology ; Complementary DNA ; cyclic AMP ; Cyclic AMP - metabolism ; Cytoplasmic inheritance ; Deoxyribonucleic acid ; DNA ; DNA - blood ; DNA - genetics ; DNA - isolation & purification ; DNA Primers ; DNA, Complementary ; Enzymes ; Exons ; Genetic mutation ; Genetics ; Glycine ; hLHR gene ; Hominidae - genetics ; hot spots ; Humans ; Isoleucine ; Leucine ; luteinizing hormone receptors ; Male ; man ; Men ; Molecular Sequence Data ; Mutation ; Physical growth ; Point Mutation ; Polymerase chain reaction ; Precocious puberty ; Protein Structure, Secondary ; puberty ; Puberty, Precocious - genetics ; Receptors ; Receptors, LH - chemistry ; Receptors, LH - genetics ; Receptors, LH - physiology ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - chemistry ; Recombinant Proteins - metabolism ; Restriction Mapping ; Signal Transduction ; Transfection
É parte de: Proceedings of the National Academy of Sciences - PNAS, 1995-03, Vol.92 (6), p.1906-1910
Notas: ObjectType-Article-2
SourceType-Scholarly Journals-1
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content type line 23
Descrição: 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 mutant 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.
Editor: United States: National Academy of Sciences of the United States of America
Idioma: Inglês

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Genetic Heterogeneity of Constitutively Activating Mutations of the Human Luteinizing Hormone Receptor in Familial Male-Limited Precocious Puberty

Laue, Louisa ; Chan, Wai-Yee ; Aaron J. W. Hsueh ; Kudo, M. ; Hsu, Sheau Yu ; Wu, Shao-Ming ; Blomberg, LeAnn ; Cutler, Gordon B.

United States: National Academy of Sciences of the United States of America

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