Mutations and polymorphisms in gonadotropin genes

Abstract

Mutations in gonadotropin genes are extremely rare. Only one case of inactivating human luteinizing hormone (LH) β mutation exists in the literature, a male with absence of Leydig cells, lack of spontaneous puberty and infertility. A total of four cases of inactivating mutation of the follicle-stimulating hormone β (FSHβ) gene (two female and two male) are known. The phenotype of the women was primary amenorrhea and absence of follicular maturation, the men were azoospermic. In addition, a common genetic variant (v) of LH was recently discovered. It is caused by two point mutations in the LH β-subunit gene, resulting in amino acid alterations: Trp 8→Arg and Ile 15→Thr. In addition, the latter change introduces an extra glycosylation signal for oligosaccharide attachment to Asn 13. The v-LHβ allele has a carrier frequency ranging from 0 to >50% in various populations. The variant LH molecule has increased intrinsic bioactivity in vitro, but decreased circulatory half-life in vivo, and the v-LHβ promoter is about 50% more active in cell line transfections than that of wild-type (wt) LH. These differences in LH synthesis and action in individuals homo- or heterozygous for the v-LH allele are reflected by altered disposition to pathologies of pituitary–gonadal function, such as delayed puberty, polycystic ovarian syndrome and infertility.