A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor gene

BACKGROUND and OBJECTIVE Mutations in the GnRH receptor (GnRH-R) gene cause hypogonadotrophic hypogonadism. Here, we present the molecular studies of the GnRH-R gene in three families with isolated hypogonadotrophic hypogonad ism. PATIENTS Three unrelated families, with at least two members diagnosed with isolated hypogonadotrophic hypogonadism were included. MEASUREMENTS DNA sequencing was performed after polymerase chain reaction a mplification of each of the three exons of the gene. RESULTS A novel homozygous missense mutation, at nucleotide 268, turning gl utamic acid into lysine, located at the second transmembrane domain of the GnRH-R gene was found in two patients pertaining to one of the families stu died. Both parents and an unaffected brother were heterozygous carriers of one mutant allele, an unaffected sister was homozygote wild type. In the ot her two affected families no mutations were found in the GnRH-R gene. CONCLUSIONS This constitutes the first description of an spontaneous mutati on located at the second transmembrane domain (Glu90Lys) of the GnRH-R, ind icating that the Integrity of glutamic acid at this position is crucial for receptor function. Also this report, complementing others, demonstrates th at mutations are distributed throughout the GnRH-R gene and that as in the only other homozygous mutation previously described, affected patients pres ent a complete form of hypogonadotrophic hypogonadism. Due to the fact that apparently consanguinity was present in our affected family, we presume th at the mutation derived from a common ancestor, by a founder gene effect.