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A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty

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Abstract

FAMILIAL male precocious puberty (FMPP) is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern1–5. Affected males generally exhibit signs of puberty by age 4. Testosterone production and Ley dig cell hyper-plasia occur in the context of prepubertal levels of luteinizing hormone (LH)3–5. The LH receptor is a member of the family of G-protein-coupled receptors6,7, and we hypothesized that FMPP might be due to a mutant receptor that is activated in the presence of little or no agonist8–12. A single A → G base change that results in substitution of glycine for aspartate at position 578 in the sixth transmembrane helix of the LH receptor was found in affected individuals from eight different families. Linkage of the mutation to FMPP was supported by restriction-digest analysis. COS-7 cells expressing the mutant LH receptor exhibited markedly increased cyclic AMP production in the absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is caused by a constitutively activated LH receptor.

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Authors and Affiliations

  1. Molecular Pathophysiology Branch, Building 10, Room 8C-101, NIDDK,

    Andrew Shenker & John J. Merendino Jr

  2. Developmental Endocrinology Branch, NICHD, Laboratory of Biochemistry and Metabolism, NIDDK, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Louisa Laue & Gordon B. Cutler Jr

  3. Cell Regulation Section, Laboratory of Biochemistry and Metabolism, NIDDK, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Shinji Kosugi

  4. Department of Laboratory Medicine, Kyoto University School of Medicine, Kyoto, 606, Japan

    Shinji Kosugi

  5. Department of Obstetrics and Gynecology, Gunma University School of Medicine, Maebashi, Gunma, 371, Japan

    Takashi Minegishi

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  1. Andrew Shenker
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  2. Louisa Laue
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  3. Shinji Kosugi
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  4. John J. Merendino Jr
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  5. Takashi Minegishi
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  6. Gordon B. Cutler Jr
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Shenker, A., Laue, L., Kosugi, S. et al. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 365, 652–654 (1993). https://doi.org/10.1038/365652a0

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