Sandra Chantot-Bastaraud

Lack of Association between Genetic Polymorphisms in Enzymes Associated with Folate Metabolism and Unexplained Reduced Sperm Counts

Background The metabolic pathway of folate is thought to influence DNA stability either by inducing single/double stranded breaks or by producing low levels of S-adenosyl-methionine leading to abnormal gene expression and chromosome segregation. Polymorphisms in the genes encoding enzymes in the folate metabolism pathway show distinct geographic and/or ethnic variations and in some cases have been linked to disease. Notably, the gene Methylenetetrahydrofolate reductase (MTHFR) in which the homozygous (TT) state of the polymorphism c.665C>T (p.A222V) is associated with reduced specific activity and increased thermolability of the enzyme causing mild hyperhomocysteinemia. Recently several studies have suggested that men carrying this polymorphism may be at increased risk to develop infertility. Methodology/Principal Findings We have tested this hypothesis in a case/control study of ethnic French individuals. We examined the incidence of polymorphisms in the genes MTHFR (R68Q, A222V and E429A), Methionine synthase reductase MTRR; (I22M and S175L) and Cystathionine beta-synthase (CBS; G307S). The case population consisted of DNA samples from men with unexplained azoospermia (n = 70) or oligozoospermia (n = 182) and the control population consisted of normospermic and fertile men (n = 114). We found no evidence of an association between the incidence of any of these variants and reduced sperm counts. In addition haplotype analysis did not reveal differences between the case and control populations. Conclusions/Significance We could find no evidence for an association between reduced sperm counts and polymorphisms in enzymes involved in folate metabolism in the French population.

Origines géniques et chromosomiques des anomalies de la spermatogenèse : aspects cliniques et rapports avec les modèles animaux

Resume Les troubles de la spermatogenese humaine apparaissent frequemment idiopathiques et peuvent alors etre dus a des causes genetiques. Des mutations touchant des genes impliques dans le controle hypothalamo-hypophysaire de la spermatogenese ont ete decrites et expliquent un certain nombre d’hypogonadismes hypogonadotropes. Les anomalies du caryotype retrouvees chez des patients infertiles sont, soit des aneuploidies touchant principalement les gonosomes X et Y, soit des anomalies de structure entrainant des troubles de la mecanique chromosomique a la meiose et le blocage des cellules germinales. Les microdeletions du chromosome Y, souvent indetectables sur le caryotype, sont responsables de la perte des genes composant le facteur AZF. La multiplication des modeles animaux mutants chez lesquels existe une infertilite mâle permettra de decrire de nouveaux genes impliques dans l’infertilite masculine humaine sous reserve que ces modeles fassent l’objet de la description detaillee de leurs relations genotype–phenotype. La prise en charge des hommes infertiles par les nouvelles techniques d’aide medicale a la procreation rend necessaire le bilan genetique de ces patients pour des raisons a la fois diagnostiques, en leur evitant par exemple des examens inutiles et pronostiques, en mesurant le risque de transmission d’une eventuelle anomalie causale a leur descendance.

Chromosome Y et infertilité masculine : qu'est-ce qu'un chromosome Y normal ?

The human Y chromosome contains a number of genes and gene families that are essential for germ cell development and maintenance. Many of these genes are located in highly repetitive elements that are subject to rearrangements. Deletion of azoospermia factor (AZF) regions AZFa, AZFb, and AZFc are found in approximately 10-15% of men with severe forms of spermatogenic failure. Several partial AZFc deletions have been described. One of these, which removes around half of all the genes within the AZFc region, appears to be present as an inconsequential polymorphism in populations of northern Eurasia. A second deletion, termed gr/gr, also results in the absence of several AZFc genes and it may be a genetic risk factor for spermatogenic failure. However, the link between these partial deletions and fertility is unclear. The gr/gr deletion is not a single deletion but a combination of deletions that vary in size and complexity and result in the absence of different genes. There are also regional or ethnic differences in the frequency of gr/gr deletions. In some Y-chromosome lineages, these deletions appear to be fixed and may have little influence on spermatogenesis. Most of these data (gene content and Y chromosome structure) have been deduced from the reference Y chromosome sequence deposited in NCBI. However, recently there have been attempts to define these types of structural rearrangements in the general population. These have highlighted the considerable degree of structural diversity that exist. Trying to correlate these changes with the phenotypic variability is a major challenge and it is likely that there will not be a single reference (or normal) Y chromosome sequence but many.

Y Chromosome Microdeletions and Haplotypes

The human Y chromosome contains a number of genes and gene families that are necessary for spermatogenesis. Many of these genes are embedded in repetitive elements that are subject to deletion events. Deletions of azoospermia factor (AZF) regions AZFa, AZFb, and AZFc are found in approx 10–15% of men with either unexplained severe oligozoospermia or azoospermia. These deletions fall on different Y chromosome backgrounds and there is no evidence for a link between a Y-chromosome lineage and the presence or absence of an AZF deletion. Several partial AZFc deletions have been described. One of these, which removes around half of all the genes within the AZFc region, appears to be present as in inconsequential polymorphism in populations of northern Eurasia. A second deletion, termed gr/gr, results in the absence of several AZFc genes and has been suggested to be a genetic risk factor for spermatogenic failure. However, the link between the gr/gr deletion and infertility is more complex. First, the gr/gr deletion is actually not a single type of deletion but a combination of deletions that vary in size and complexity and result in the absence of different members of the deleted azoospermia (DAZ) gene family as well as other AZFc genes, such as CDY1. Second, there are regional or ethnic differences in the frequency of gr/gr deletions. In some Y-chromosome lineages, these deletion appear to be fixed and may have little influence on spermatogenesis. Third, these observations have influenced a number of association studies aimed to determine the relationship between the gr/gr deletion and male infertility. Consequently, some studies suggest that the gr/gr deletion confers a strong genetic susceptibility to reduced sperm counts, whereas others suggest that the genetic susceptibility may not exist or be limited to specific Y-chromosome haplotypes.