An Encore for the Repeats: New Insights into an Old Genetic Variant

Abstract

Throughout the human genome there are trinucleotide repeat sequences susceptible to either expansion or contraction during replication, giving rise to length polymorphisms in the general population. The polymorphic CAG repeat, which encodes an uninterrupted polyglutamine (polyQ) tract in the N-terminal transactivation domain of the androgen receptor (AR), is the most extensively studied genetic variant in individuals with disorders of the male reproductive system. Despite an impressive number of studies, the pathogenic role of this polymorphism and its clinical relevance are still a matter of debate. Although a recent meta-analysis of 33 publications (1) supports a pathogenetic role for longer polyQ length in male infertility, the authors conclude their work stating that there is a need for new, welldesigned studies (1). In fact, available data do not allow us to establish what range of AR-CAG repeat lengths predisposes impaired sperm production or to estimate the entity of the associated risk (1). Similar to other genetic variants, the literature related to CAG repeats suffers from an abundance in conflicting case-control association studies and a paucity of functional data (2). There are several plausible explanations for these apparent controversies, mostly related to: 1) poor study design (inappropriate selection of patients and controls, particularly with respect to their phenotype and their ethnic/geographic origin, and underpowered size of the study population); and 2) intrinsic complexity of the interaction between the AR and its endogenous/environmental ligands. An additional intricacy derives from the presence of another polymorphic trinucleotide repeat, (GGN)n, in the first exon of the AR gene, which may modulate the functional effect of the CAG repeat length, stressing the need for a combined analysis of the two AR polymorphisms (3, 4). It is commonly accepted that the length of the polyQ tract influences the transactivation capacity of the receptor in an inverse manner; that is, the longer the tract, the lower the activity. To support this hypothesis, a clear negative impact on AR activity is documented in relationship with pathological expansions of the repeat length (40 or more), known as the Kennedy syndrome (5). This syndrome is characterized by spinobulbar muscular atrophy and hypoandrogenism due to partial androgen insensitivity. On the other hand, controversies still exist about the effect of variations in polyQ within the normal polymorphic range. The normal distribution of the (CAG)n is reported as 6–39 repeats, with a median of 21–22 in White Caucasian, 19–20 in African-American, 22–23 in Asian, and 23 in Hispanic populations. Clinical observations showing a linear correlation between testosterone level and CAG repeat length support the notion of a functional effect of the polymorphism within the normal range. In fact, increased circulating testosterone and estradiol levels in men with a higher number of CAG repeats can be considered as a compensatory mechanism aimed to overcome the weaker AR activity (6, 7). However, such a linear correlation has not been clearly demonstrated by in vitro experiments. The first two functional studies reported that the longest tract (Q31) displayed lower activity when compared with the shortest one (Q15). However, no significant differences were observed by comparing these two types of alleles to an intermediate number of CAG repeats (20 or 24) (8, 9). Quite strikingly, two recent articles provided evidence for the lack of a stepwise reduction in activity with increasing CAG length across the polymorphic