A single case report from this institution described a male who had an inactivating mutation of the LH-P subunit (99). The proband presented at the age of 17, with delayed puberty. He was from a family with several infertile male members. T levels were reduced in association with elevated LH and FSH levels. Testicular biopsy revealed spermatogenic arrest and absent Leydig cells. Long-term hCG therapy induced testicular growth and spermatogenesis. The mutant hormone had normal immunoreactivity but no biologic activity. These findings, together with the occurrence of infertility in three maternal uncles, suggested a genetic defect in the LH structure. A homozygous mutation of the LH-P subunit, A to G missense mutation, was found in codon 54, causing a Glu to Arg substitution. The proband's mother, sister, and uncles were heterozygous for the mutation. Coexpression of the mutated LH-P gene with the normal a-subunit gene in CHO cells resulted in the formation of immunoreactive LH a/p heterodimers, with no biological activity because of its inability to bind to the LH receptor. This rare case confirms that LH is not needed in utero for a normally masculinized fetus at birth; instead, placental hCG stimulates androgen production by the fetal testis. However, after birth, the endocrine function of the testis critically depends on LH, as demonstrated by the total absence of pubertal development in this case without bioactive LH.
Recently, two men with FSH-P subunit mutations have been described. The first subject, a 32-yr-old man, appeared normally virilized with normal LH and T levels but small testes, azoospermia, and undetectable FSH level (100). Genetic analysis revealed a homozygous T to C mutation (Cys 82 to Arg). It was predicted that the lack of cys-teine would result in the inability to form the proper disulfide bond of FSH-P with abnormal tertiary structure. The second reported case of an FSH-P gene mutation is an 18-yr-old man who presented with delayed puberty, small testes (1 and 2 mL), azoospermia, and undetectable FSH levels. The finding of a high LH and low T levels implies an additional unexplained defect in Leydig cell function (101). Genetic analysis demonstrated a homozygous 2 bp deletion in codon 61. The mutation gives rise to an altered amino acid sequence, followed by a premature stop codon. Consequently, the translated FSH-P protein was truncated and unable to associate with the a-subunit, and serum FSH was undetectable.
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