Only one totally inactivating mutation of the LHfi gene has so far been detected (27) (Table 1). The proband was a male who presented with delayed puberty at the age of 17 yr and had a family history of male infertility on the father's side, but none on the mother's side. His serum testosterone level was low and immunoreactive LH was high. A normal serum testosterone response was found on challenge with exogenous hCG, but in vitro bioassay of serum LH revealed no activity. These findings, together with a family history of consanguinity, suggested an inherited defect in the LH structure, maintaining its immunoreactivity but abolishing bioactivity. After 2 yr of testosterone treatment, there was no evidence for spontaneous puberty after treatment was withdrawn. Testicular biopsy revealed arrested spermatogenesis and absent Leydig cells. Long-term hCG treatment resulted in testicular enlargement, normal virilization, and spermatogenesis.
Sequencing of the patient's LHfi subunit gene revealed a homozygous A-to-G missense mutation in codon 54, causing a glutamine (Gl) to arginine (Arg) substitution. The proband's mother, sister, and three uncles were heterozygotes for the same mutation. A gene conversion within the CGP/LHP gene cluster was excluded, which indicated that the alteration in LHfi structure represented a spontaneous germ line mutation. When the mutated LHP was coexpressed with normal a-subunit in CHO cells, immunoreactive LH a/p heterodimers were formed, but they displayed no activity in a radioreceptor assay, i.e., the mutated hormone was devoid of biological activity because of its inability to bind to LH-R. The heterozygous family members, as expected, had reduced ratio of bioactivity/immunoreactivity of their serum LH, because half of this protein was encoded by the mutated gene.
This rare case clarifies some points about pituitary LH's developmental role. Because the affected man was apparently normally masculinized at birth and had descended testes, pituitary LH is not needed for the stimulation of testicular testosterone or INSL-3 production in utero. Indeed, fetal testicular testosterone production is initiated seemingly autonomously but becomes subsequently dependent on placental hCG (15,41), and fetal pituitary LH plays a minimal role in utero. However, the endocrine function of the postnatal testes is critically dependent on pituitary LH, as was demonstrated by the total absence of mature Leydig cells and spontaneous puberty in this patient who was lacking bioactive LH. It is intriguing that the prevalence of infertility was increased in heterozygous male family members, despite normal pubertal mas-culinization. Inasmuch as the proband's father was an obligate heterozygote, however, the importance of the heterozygosity for testicular function remains uncertain.
The heterozygous women, including the proband's mother, were asymptomatic. It is curious that no other human subjects homozygous for this type of mutation have been subsequently detected, and, although the phenotype of the single patient is in harmony with our knowledge of the ontogeny of LH action, some caution must be exercised when drawing conclusions on the basis of a single patient. The female phenotype would probably resemble those with inactivating LH-R mutation (see section on LH-R mutations). Comparison of these two conditions would elucidate the role of intrauter-ine LH/hCG action, if any, in ovarian development and function.
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