Molecular Human Reproduction, Vol. 8, No. 3, 286-298,
March 2002
© 2002 European Society of Human Reproduction and Embryology
Reproductive genetics |
High frequency of DAZ1/DAZ2 gene deletions in patients with severe oligozoospermia
1 Reproduction Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany, 2 Department of Human Genetics, Faculty of Medicine, University of Porto, Porto, 3 National Institute of Health Dr. Ricardo Jorge, Human Genetics Center, Lisboa, Portugal, 4 Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, 5 Department of Andrology, University of Marburg, Marburg, Germany and 6 Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
Abstract
Deletions of the DAZ gene family in distal Yq11 are always associated with deletions of the azoospermia factor c (AZFc) region, which we now estimate extends to 4.94 Mb. Because more Y gene families are located in this chromosomal region, and are expressed like the DAZ gene family only in the male germ line, the testicular pathology associated with complete AZFc deletions cannot predict the functional contribution of the DAZ gene family to human spermatogenesis. We therefore established a DAZ gene copy specific deletion analysis based on the DAZ-BAC sequences in GenBank. It includes the deletion analysis of eight DAZ-DNA PCR markers [six DAZ-single nucleotide varients (SNVs) and two DAZ-sequence tag sites (STS)] selected from the 5' to the 3'end of each DAZ gene and a deletion analysis of the gene copy specific EcoRV and TaqI restriction fragments identified in the internal repetitive DAZ gene regions (DYS1 locus). With these diagnostic tools, 63 DNA samples from men with idiopathic oligozoospermia and 107 DNA samples from men with proven fertility were analysed for the presence of the complete DAZ gene locus, encompassing the four DAZ gene copies. In five oligozoospermic patients, we found a DAZ-SNV/STS and DYS1/EcoRV and TaqI fragment deletion pattern indicative for deletion of the DAZ1 and DAZ2 gene copies; one of these deletions could be identified as a `de-novo' deletion because it was absent in the DAZ locus of the patient's father. The same DAZ deletions were not found in any of the 107 fertile control samples. We therefore conclude that the deletion of the DAZ1/DAZ2 gene doublet in five out of our 63 oligozoospermic patients (8%) is responsible for the patients' reduced sperm numbers. It is most likely caused by intrachromosomal recombination events between two long repetitive sequence blocks (AZFc-Rep1) flanking the DAZ gene structures.
AZFc/DAZ deletions/DAZ-SNVs/male infertility/oligoazoospermia
Notes
7 To whom correspondence should be addressed at: Im Neuenheimer Feld 328, D-69120 Heidelberg, FRG, Germany. E-mail: peter_vogt{at}med.uni-heidelberg.de
Recently, a reduced number of DAZ gene copies in subfertile and infertile men has also been reported by de Vries et al. (2002, Fertil. Steril., 77, 68–75), using DAZ-SNV deletion and DAZ-Fibre-FISH experiments. Surprisingly, the Fibre-FISH experiments did not support their SNV deletion analyses and Fibre-FISH was also not able to distinguish between the deletion of one DAZ gene copy and the deletion of a complete DAZ gene cluster (DAZI/DAZ2 or DAZ3/DAZ4, respectively). To confirm partial DAZ gene deletions, the use of DYS1 blot experiments instead of Fibre-FISH, as proposed in this paper, is therefore strongly recommended.
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