Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism

Mutations in the GnRH receptor (GNRHR) have been described as a cause of re productive failure in a subset of patients with idiopathic hypogonadotropic hypogonadism (IHH). Given the apparent rarity of these mutations, we set o ut to determine the frequency and distribution of GNRHR mutations in a hete rogeneous population of patients with IHH who were well characterized with respect to diagnosis, phenotype, and mode of inheritance and to define thei r distribution within the receptor protein. One hundred and eight probands with IHH were screened for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sens e of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann synd rome). Exon segments in the GNRHR were screened for mutations using tempera ture gradient gel electrophoresis, and all mutations were confirmed by dire ct sequencing. Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inh eritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patien ts with normosmic, autosomal recessive IHH. The remaining 3 probands with G NRHR mutations were from a subgroup of 18 patients without evidence of fami lial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients wi th sporadic IHH and a normal sense of smell. Among the five individuals bearing GNRHR mutations, a broad spectrum of phe notypes was noted, including testicular sizes in the male that varied from prepubertal to the normal adult male range. Three probands had compound het erozygous mutations, and two had homozygous mutations. Of the eight DNA seq uence changes identified; four were novel: Thr(32)Ile, Cys(200)Tyr, Leu(266 )Arg, and Cys(279)Tyr. COS-7 cells transiently transfected with complementa ry DNAs encoding the human GNRNR containing each of these four novel mutati ons failed to respond to GnRH agonist stimulation. We conclude that 1) the spectrum of phenotypes in patients with GNRHR mutat ions is much broader than originally anticipated; 2) the frequency of GNRNR mutations may be more common than previously appreciated in familial cases of normosmic IHH and infrequent in sporadic cases; and 3) functional mutat ions of the GNRHR are distributed widely throughout the protein.