In individuals with familial male precocious puberty (FMPP; 176410) from 8 different families, Shenker et al. (1993) identified heterozygosity for a single A-to-G transition that resulted in substitution of glycine for aspartate at position 578 (D578G) in the sixth transmembrane helix of the LH receptor. Linkage of the mutation to the clinical disorder 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 this disorder is caused by a constitutively activated LH receptor.
Kosugi et al. (1995) stated that the asp578-to-gly mutation had been found in affected males from 9 American FMPP families. Since 7 of the 9 originated in the southeastern United States, the possibility of a shared common ancestor was raised. For that reason, they analyzed genomic DNA from affected males from 6 new FMPP families: 2 from Germany, 3 from France, and 1 from the western United States with mixed Caucasian-Native American ancestry. None of the 6 new samples contained the asp578-to-gly mutation, as indicated by the absence of digestion with MspI. PCR products were then screened for heterozygous mutations by temperature-gradient gel electrophoresis. DNA fragments from 2 of the patients migrated abnormally. Direct sequencing of the PCR product from 1 affected German male revealed a heterozygous mutation of the type described in another European family by Kremer et al. (1993); see 152790.0002.
In a screening of genomic DNA from 32 unrelated families with male-limited precocious puberty, Laue et al. (1995) found that 28 had the inherited form of the disorder, and of these, 24 had the D578G mutation. Four additional mutations were found among the remaining 4 families with the inherited form and in 4 sporadic cases of the disorder.
Yano et al. (1994) found the asp578-to-gly mutation in a sporadic case of male precocious puberty in a Japanese patient.
Kawate et al. (1995) found this same constitutively activating mutation of the LHCGR gene in a family with male-limited gonadotropin-independent precocious puberty (testotoxicosis). The family was ascertained through 2 affected brothers whose father had started puberty before his third birthday. His maternal uncle and maternal great uncle were also affected.
Rosenthal et al. (1996) evaluated the pituitary-gonadal axis in a mother after 2 of her sons with familial male-limited precocious puberty were found to have the constitutively activating D578G mutation of the LHCGR gene. Ovarian function was normal in the 36-year-old mother as assessed by LH dynamics and FSH and androgen levels were normal throughout her menstrual cycle. Hormonal responses to acute GnRH agonist (nafarelin) challenge, chronic GnRH agonist administration, and dexamethasone were also normal. Studies of the affected sons on presentation at 2.4 and 3.5 years of age revealed that acute LH responses to nafarelin were in the hypogonadotropic range, and the FSH responses were prepubertal despite the presence of late pubertal testosterone blood levels. These data showed that the activating D578G mutation does not cause functional ovarian hyperandrogenism but only incomplete pubertal activation of Leydig cells consistent with the relatively low constitutive activity of this mutation.
Martin et al. (1998) reported the development of a testicular seminoma in a 35-year-old man who had previously been diagnosed with familial male-limited precocious puberty and found to be heterozygous for the gain-of-function D578G mutation in the LHCGR gene. The authors stated that this represented the first case of a testicular germ cell tumor described in an FMPP patient.
