The luteinizing hormone/chorionic gonadotropin (LH/CG) receptor (hLHR) plays a critical role in human reproduction. Mutations of the hLHR gene have been identified as the cause of two human diseases. Studies of polymorphisms of the hLHR gene will be useful in tracking the defective gene in families with these disorders. To investigate the polymorphism of the hLHR gene, exons containing the entire coding sequence of the hLHR gene were amplified by independent polymerase chain reactions (PCR) using genomic DNA derived from unrelated individuals as templates. Nucleotide sequence of single stranded DNAs generated by asymmetric PCR was determined by Sanger's dideoxy chain termination method. A CTGCAG insertion was found in exon 1 after nucleotide 54 in 7 of 26 independent chromosomes examined. The heterozygote frequency was 0.385. This insertion introduced a Leu-Gln dipeptide into the first Leucine repeat of the hLHR extracellular domain. Apparently, this insertion had no effect on the biological activity of the hLHR. Exon 10 contained two polymorphisms which also changed the encoded amino acids. Among 54 chromosomes analyzed 64% were A and 35.2% were G at nucleotide 872 with a heterozygote frequency of 0.115. The A allele gave rise to a codon for Asn and the creation of a potential N-glycosylation site. The substitution of A by G led to the replacement of Asn by Ser. This amino acid difference had no effect on the activity of the hLHR indicating that either this site was not glycosylated or glycosylation at this site had no effect on the activity of the receptor. The other polymorphism occurred at nucleotide 935. Fifty nine percent of chromosomes examined were A and 41% were G at this site with the encoded amino acid being Ser in the former and Asn in the latter. The heterozygote frequency was 0.192. This polymorphism did not have biological consequence. Both of the exon 10 polymorphisms showed ethnic prevalency. The 872 G allele and the 935 A allele were found predominantly in non-Caucasians. Another polymorphism was detected in exon 11. Nucleotide 1065 was C in 60% and T in 40% of the 50 chromosomes examined. This polymorphism was neutral and did not alter the amino acid encoded. This work was supported in part by NIH grant HD31553.

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