Abstract
Luteinizing hormone (LH) plays its effects on ovarian and testicular cells through binding to a specific cell surface receptor. We recently described two kindreds with LH resistance due to abnormalities of the LH receptor (LH-R) gene. Affected XY members presented with severe or mild fetal undermasculinization (female external genitalia or micropenis) and primary hypogonadism, while an XX affected member showed normal pubertal development, increased plasma concentrations of LH, and amenorrhea. The first kindred included three XY phenotypic female siblings with Leydig cell hypoplasia and primary hypogonadism and a fully developed XX sister with elevated plasma concentrations of LH and amenorrhea. PCR amplification of genomic DNA and direct sequencing of the entire exon 11 of the LH-R revealed that all four affected individuals had a homozygous mutation (Arg554-->Stop codon) in the third cytosolic loop of the LH-R, which resulted in a truncated LH-R unable to transduce the hormonal signal. The second kindred included a 6-year-old XY boy with a micropenis and bilaterally descended testes, who demonstrated no response to exogenous human chorionic gonadotrophin postnatally. This patient had a nonconservative homozygous amino acid substitution (Ser616-->Tyr616) in the seventh transmembrane domain of his LH-R gene that was inherited from his heterozygous parents. The mutant receptor expressed in heterologous cells in vitro demonstrated no appreciable binding of 125I-labeled hLH, nor did it confer cAMP responsiveness to LH. Homozygous inactivating mutations of the LH-R cause complete or mild testicular failure in genetic males, resulting in female external genitalia or micropenis and primary hypogonadism. Similar mutations in genetic females may cause failure of ovulation and corpus luteum formation, resulting in amenorrhea. Follicular growth and development are apparently sufficient to allow feminization at puberty.
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