HETEROGENEITY OF ACTIVATING MUTATIONS OF THE HUMAN LUTEINIZING-HORMONE RECEPTOR IN MALE-LIMITED PRECOCIOUS PUBERTY

Male-Limited precocious puberty (MPP) is a gonadotropin-independent di sorder that occurs sporadically or is inherited in an autosomal domina nt, male-limited pattern, Recent studies have identified constitutivel y activating missense mutations in the human luteinizing hormone recep tor (hLHR) gene leading to Leydig cell activation and precocious puber ty. Patients with sporadic MPP (SMPP) or with different ethnic backgro unds appear to have a greater likelihood of having novel mutations, In the current study we examined genomic DNA from two unrelated cases of SMPP of African-American descent for novel mutations of the hLHR gene . A heterozygous A to C transversion at nucleotide 1723 resulting in s ubstitution of Leu for lle575 in transmembrane helix 6 was identified. Human embryonic kidney cells transfected with cDNA for the mutant hLH R-I575L, created by polymerase chain reaction-based mutagenesis of the wild-type (hLHR-wt) cDNA, exhibited increased basal levels of cAMP pr oduction in the absence of agonist, indicating constitutive activation . Surface expression of hLHR-I575L, as reflected by human chorionic go nadotropin binding, was diminished compared to hLHR-wt, while agonist affinity was unaffected. With the exception of two polymorphic bases, no mutation was identified within the coding sequence of the hLHR in t he second case of SMPP, We conclude that I575L is a unique constitutiv ely activating mutation that impairs cell surface expression of the re ceptor but does not alter agonist affinity. Furthermore, mutations of the hLHR gene causing SMPP are highly heterogeneous and may be found i n regions other than exon 11 of the hLHR. Last, patients with MPP from different ethnic backgrounds are likely to have novel mutations. (C) 1996 Academic Press, Inc.