Mutations and polymorphisms in the gonadotrophin genes; clinical relevance.

Recent studies on molecular pathogenesis of reproductive disorders have demonstrated an important genetic component in subfertility and infertility. The current methods of molecular biology, enabling detailed identification of mutations and polymorphisms, have revealed numerous mutations in the key genes involved in regulation of the reproductive functions. A good example are the common microdeletions that are detectable in the Y chromosome of azoospermic and oligozoospermic men (see, e.g. Najmabadi et al., 1996; Foresta et al., 1997; Kremer et al., 1997). When genes involved in hormone action are mutated, the phenotypic consequences are determined by the nature of the mutation. In a gain-of-function mutation, heterozygosity is sufficient to produce a phenotype, whereas in loss-of-function mutations usually only the homozygotes are affected. Both types of mutations are known with the receptor genes, but those of the ligands, i.e. hormones, are almost always of the loss-of-function type. When the genes involved in reproductive functions are affected, it is possible, but still rarely proven, that a given mutation affects the fertility of only one sex. Although the mutations impairing fertility should be self-limiting, they stay in the genetic pool due to their variable mode of inheritance and penetrance, and are in fact more common than assumed. Concerning gonadotrophins, the key hormones of the hypothalamic-pituitary-gonadal axis, microheterogeneity, due to variability in their carbohydrate structures, has been known for a long time. This phenomenon has been found to alter the intrinsic bioactivity of gonadotrophins, and in some cases to result in pathologies of gonadal function (Dufau & Veldhuis, 1987; Beitins & Pabmanabhan, 1991; Tsatsoulis et al., 1991). The variability of gonadotrophin glycosylation has usually been considered to be hormonally regulated, and its eventual genetic basis remains totally unknown. Our recent studies on bioactivity/immunoreactivity ratios of gonadotrophins (especially of LH) in various physiological and pathophysiological conditions have shown that this parameter varies much less than previously demonstrated, and probably has less clinical value than proposed (Jaakkola et al., 1990; Huhtaniemi et al., 1992, 1996). With regard to genuine mutations of the gonadotrophin genes, surprisingly few reports still exist. Since such mutations would severely compromise fertility, they are apparently sporadic and will be rapidly eliminated from the genetic pool. In contrast, a surprisingly common genetic variant of LH (v-LH) was recently described. It alters the functional characteristics of LH, and is likely to be an important contributing factor in the individual physiological variation of LH action and in some pathologies of the pituitary-gonadal function. The purpose of this review is to summarize our current knowledge on mutations of gonadotrophin genes and the common genetic variant of LH. In addition, we review the data obtained from experimental studies on targeted disruption of the gonadotrophin subunit genes in mice, since these genetically modified animal models are very informative as regards the role of gonadotrophins in reproductive functions.