COSEGREGATION OF MISSENSE MUTATIONS OF THE LUTEINIZING-HORMONE RECEPTOR GENE WITH FAMILIAL MALE-LIMITED PRECOCIOUS PUBERTY

Familial male-limited precocious puberty is a male-limited autosomal d ominant condition. It is characterized by increased testosterone synth esis in the absence of testicular stimulation by luteinizing hormone ( LH). We hypothesised that an abnormal configuration of the LH receptor might autonomously activate G protein coupling, and thereby cause the overproduction of testosterone in this condition. To test this hypoth esis, we screened for mutations in a part of the LH receptor gene that is important for G protein binding. DNA sequence variation was detect ed in 2 out of 5 families with male-limited precocious puberty by the single strand conformation polymorphism technique. Direct sequencing d emonstrated different single nucleotide substitutions in the sixth tra nsmembrane region of the LH receptor gene. The mutations cosegregated with the disorder in both families (lod score 5.76 without recombinati on). Both mutations cause an amino acid substitution in the sixth tran smembrane domain, close to the C-terminal portion of the third cytopla smatic loop, a region which is important for the binding of G proteins . We conclude that familial male-limited precocious puberty cosegregat es with missense mutations in the LH receptor gene. These findings sup port the hypothesis that increased activity of the LH receptor is the pathogenetic mechanism that causes the abnormal pubertal development i n this condition.