A missense (T577I) mutation in the luteinizing hormone receptor gene associated with familial male-limited precocious puberty

Familial male-limited precocious puberty (FMPP) is a condition where only males are affected, manifesting puberty prematurely due to autonomous hyperfunction of Leydig cells. This is triggered by constitutive activation of the luteinizing hormone receptor (LHR) or its downstream G-protein-coupled metabolic pathways. Previous studies have identified missense mutations in the LHR gene that induce FMPP by altering the receptor's functional dynamics. In this study, we report a novel T577I missense mutation in a Sardinian family, affecting the father and his 15-month-old son, both presenting similar early-onset puberty. DNA sequencing revealed a heterozygous C-to-T transition at nucleotide 1738 in the LHR gene, resulting in a threonine to isoleucine substitution at codon 577. This mutation is situated within the critical sixth transmembrane domain of the LHR, adjacent to other previously identified mutations linked to receptor activation. Functional implications suggest that this substitution may enhance receptor activation by modifying its interaction with G-proteins, thereby upregulating intracellular cAMP levels and testosterone production. The mutation's rarity and its absence in 60 unrelated controls underscore its likely pathogenic role in FMPP. This discovery adds to the understanding of the genetic basis of FMPP and assists in the diagnostic evaluation of precocious puberty.