Luteinizing hormone receptor mutations in disorders of sexual development and cancer

Human male sexual development is regulated by chorionic gonadotropin (CG) a nd luteinizing hormone (LH). Aberrant sexual development caused by both act ivating and inactivating mutations of the human luteinizing hormone recepto r (LHR) have been described. All known activating mutations of the LHR are missense mutations caused by single base substitution. The most common acti vating mutation is the replacement of Asp-578 by Gly due to the substitutio n of A by G at nucleotide position 1733. All activating mutations are prese nt in exon 11 which encodes the transmembrane domain of the receptor. Const itutive activity of the LHR causes LH releasing hormone-independent precoci ous puberty in boys and the autosomal dominant disorder familial male-limit ed precocious puberty (FMPP). Both germline and somatic activating mutation s of the LHR have been found in patients with testicular tumors. Activating mutations have no effect on females. The molecular genetics of the inactiv ating mutations of the LHR are more variable and include single base substi tution, partial gene deletion, and insertion. These mutations are not local ized and are present in both the extracellular and transmembrane domain of the receptor. Inactivation of the LHR gives rise to the autosomal recessive disorder Leydig cell hypoplasia (LCH) and male hypogonadism or male pseudo hermaphroditism. Severity of the clinical phenotype in LCH patients correla tes with the amount of residual activity of the mutated receptor. Females a re less affected by inactivating mutation of the LHR. Symptoms caused by ho mozygous inactivating mutation of the LHR include polycystic ovaries and pr imary amenorrhea.