GENETIC-HETEROGENEITY EVIDENCED BY LOW INCIDENCE OF KAL-1 GENE-MUTATIONS IN SPORADIC CASES OF GONADOTROPIN-RELEASING-HORMONE DEFICIENCY

Isolated GnRH deficiency is a heritable condition characterized by a f unctional deficit in GnRH secretion. Familial cases with different mod es of inheritance have been described, and the gene responsible for th e X-linked form (KAL-1) has been identified. However, sporadic cases w ith no documented family history of GnRH deficiency account for the ma jority of the affected patients. For this reason, we sought to determi ne the frequency with which KAL-1 gene mutations occur in patients wit h sporadic GnRH deficiency. Only 1 of 21 patients with sporadic GnRH d eficiency was found to bear a defect in the KAL-1 gene (a deletion of 14 bases starting at codon 464). Three types of polymorphic single bas e substitutions with no apparent correlation with GnRH deficiency were also detected in several patients. In each of 3 different patients wi th an X-linked mode of inheritance, 3 genetic defects, 2 point mutatio ns and a small intragenic deletion, were detected. These defects consi st of a single base mutation introducing a stop codon at position 328, a single base mutation resulting in a phenylalanine to leucine substi tution at position 517, and a 9-base deletion at the 3'-exon-intron sp lice site of exon 8, respectively. All identified genetic defects occu r within the fibronectin type III repeats of the predicted protein enc oded by the KAL-1 gene. In conclusion, our study indicates that the in cidence of genetic defects within the coding region of the KAL-1 gene in patients with sporadic GnRH deficiency is low (5-8%), thus supporti ng the idea that the X-linked form of inheritance represents the least common form of the disease.