Familial male precocious puberty (FMPP) is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. Affected males generally exhibit signs of puberty by age 4. Testosterone production and Leydig cell hyperplasia occur in the context of prepubertal levels of luteinizing hormone (LH). The LH receptor is a member of the family of G-protein-coupled receptors, and we hypothesized that FMPP might be due to a mutant receptor that is activated in the presence of little or no agonist. 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.

We established the first extensive database for Asian patients with MEN1. Although the clinical features of Japanese patients were similar to those in western countries, there were several characteristic differences between them.

Multiple endocrine neoplasia (MEN) type 2B is a clinically distinct entity among the autosomal dominant MEN 2 syndromes. Most patients with MEN 2B carry a germline mutation (M918T) of the RET proto‐oncogene, while a few carry A883F. We examined a patient with MEN 2B, but without M918T or A883F, and her relatives. Here, we report the presence in this patient of 2 germline mutations, V804M and Y806C in the same allele. While the novel Y806C was inherited from her father, its carriers (her father and brother) was not affected by MEN 2. In contrast, V804M was a de novo mutation, that has been reported in patients with familial medullary thyroid carcinoma. Combinations of mutations of the RET proto‐oncogene may cause oncogenic activities different from those of single mutations.

A constitutively activating mutation encoding Asp 578 3 Gly in transmembrane helix 6 of the lutropin/ choriogonadotropin receptor (LHR) is the most common cause of gonadotropin-independent, male-limited precocious puberty. This mutant LHR produces a 4.5-fold increase in basal cAMP when expressed in COS-7 cells. To better understand the normal role of Asp 578 in the LHR we studied the effect of seven other amino acid substitutions at this position. No agonist binding or response was detected with the Asp 578 3 Pro mutant. Agonist binding affinity was unaffected by the other substitutions and estimated receptor concentrations ranged from 11 to 184% of wild type. Substitution of Asp 578 with Asn, a similarly sized, uncharged residue, did not produce agonist-independent activation. In contrast, replacement with Glu, Ser, or Leu caused 4.9 -5.6-fold stimulation of basal cAMP. Substitution with Tyr (8.5-fold) or Phe (7.5-fold) had a greater activating effect. Only the Tyr, Phe, and Leu mutants showed constitutive activation of the inositol phosphate pathway. Our data suggest that it is the ability of the Asp 578 side chain to serve as a properly positioned hydrogen bond acceptor, rather than its negative charge, that is important for stabilizing the inactive state of the LHR. A bulky aromatic side chain at position 578 may further destabilize the inactive receptor conformation.

Aggressive resection surgery based on accurate localization with the SASI test was useful for biochemical cure of gastrinoma in patients with MEN 1.