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Uva-DARE (Digital Academic Repository) UvA-DARE (Digital Academic Repository) The DAZ genes and impaired spermatogenesis de Vries, J.W.A. Publication date 2002 Link to publication Citation for published version (APA): de Vries, J. W. A. (2002). The DAZ genes and impaired spermatogenesis. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:29 Sep 2021 Chapterr 4 REDUCEDD COPY NUMBER OF DAZ GENES IN SUBFERTILE AND INFERTILE MEN. |ann W.A. de Vriesa, Mariëtte J.V. Hofferdb, Sjoerd Repping^, Jan M. N, Hoovers5,, Nico J. Leschotb and Fulco van der Veend. 'Centerr for Reproductive Medicine, Academic Medical Center, Amsterdam, The Netherlands s bb Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands s Fertilityy and Sterility 2002;77: 68-75 Chapterr 4 Abstract t Objective(s):: To determine the copy number and identity of the DAZ genes on the YY chromosomes of infertile patients. Design:: Prospective study. Setting:: University medical center. Patient(s):: One hundred and thirty-nine patients with male factor infertility. Intervention(s):: The separate genes were detected by polymerase chain reaction (PCR)) digestion assays of sequence family variants in leukocyte DNA and by fluorescencee in situ hybridization of interphase nuclei and chromatin fibers. Mainn Outcome Measure(s): Number of DAZ genes present. Result(s):: One hundred twenty-nine patients had four genes, 6 patients had two genes,, and 4 patients had none. Three patients had a deletion of the two proximal DAZDAZ genes, and three were missing both distal genes. Semen analysis showed a lesss severe phenotype in patients with only two DAZ genes compared with patientss missing all four genes. Conclusion(s):: In six patients, two different partial deletions were found that were nott detected by PCR with conventional markers. One patient with an AZFb deletionn appeared to also have a partial AZFc deletion that was not detected by routinee PCR. Phenotypic differences between patients with different deletions suggestt a dose effect of the DAZ genes Keyy Words: DAZ genes, partial deletions, AZFc, Y chromosome, male subfertility. Reducedd copy number INTRODUCTION N Too date, 10 gene families located on the non-recombining region of the Y chromosomee that are specifically expressed in the testis have been described (1, 2).. The number of copies per gene family varies. RBMY, for instance, has many copiess that are dispersed over the entire length of the Y chromosome, of which onlyy one to four seem to be needed for spermatogenesis (3-5). The DAZ gene familyy consists of four copies located relatively close together in deletion interval 66 on chromosome band Yq11, designated as AZFc. As we demonstrated using fluorescencee in situ hybridization (FISH), the four copies are located in two clusters,, each comprising an inverted pair of DAZ genes (6). At least three different DAZDAZ complementary DNAs have been identified, indicating that at least three DAZDAZ genes are transcribed in the testis during spermatogenesis (6, 7). Becausee DAZ genes have multiple copies, sequence tagged site markers locatedd in the DAZ genes tend to also have multiple copies. Polymerase chain reactionn (PCR) analysis with conventional markers, the method used in all publishedd deletion studies thus far, does not detect individual gene deletions withinn the DAZ gene family. Therefore, subfertile or infertile men may carry a deletionn of fewer than four of the DAZ genes that goes undetected by conventionall PCR techniques. Thee number of DAZ genes present can be determined by using FISH and gene-specificc PCR digestion assays. Fluorescence in situ hybridization on interphasee nuclei allows detection of the separate gene clusters, and FISH on extendedd DNA fibers (also called "fiber FISH") can be used to detect the separate geness within the clusters. A gene-specific PCR digestion assay that identifies the fourr different DAZ genes by their sequence family variants was recently developed (6).. It makes use of single nucleotide variants in three different sequence tagged sitess in the DAZ genes. These variants can be identified by using PCR digestion assays,, producing a specific band pattern for each DAZ gene (the so-called DAZ 67 7 Chapterr 4 genee signature) that identifies the four different DAZ genes (6). Deletions of all fourr DAZ genes have been described and are associated with azoospermia or severee oligozoospermia (8, 9). AA partial deletion of the DAZ genes was recently described in a subfertile patientt (10). It is not known how frequently this partial deletion is detected in subfertilee or infertile men. We therefore examined the number of DAZ genes in patientss with variable semen characteristics, all of whom had diagnosed male factorr subfertility or infertility, by using gene-specific sequence family variant PCR andd FISH. To determine whether different phenotypes in these patients are associatedd with the number of DAZ genes present, we related the number of copiess found to semen characteristics. MATERIALSS AND METHODS PATIENTSS AND SEMEN DONORS. Fromm October 1997 to December 1998, we enrolled 139 consecutive patientss attending our clinic in whom male factor subfertility or infertility had beenn diagnosed. Semen analysis was performed according to World Health Organizationn criteria (11). To be included, patients had to have no history of alcoholl abuse, orchitis, surgery on the vasa deferentia, bilateral orchidectomy, chemotherapy,, radiotherapy, or obstructive azoospermia (confirmed by testis biopsy).. An andrologic history was taken, testicular volume was measured, and bloodd was collected for karyotyping and DNA isolation. Blood from semen donors withh proven fertility attending our semen bank was used as an internal control. Thee study was approved by the institutional review board, and all patients and semenn donors gave informed consent before participating. 68 8 Reducedd copy number CONVENTIONALL PCR ASSAYS. Isolatedd DNA from leukocytes obtained by venipuncture was examined by usingg routine PCR amplification to detect deletions of the following loci: sY81, sY84,, SY182, sY94, sY102, sYl 1 7, sY143, sY147 sYl 52, sY1 53, and sYl 57. SEQUENCEE FAMILY VARIANTS. Sequencee family variants that distinguish among DAZ genes were detected byy PCR amplification of the three sequence tagged site markers sY581 (intron 3), sY5866 (intron 6), and sY587 {intron 10). This was followed by enzyme digestion, ass described elsewhere (6). Figure 1 shows the nucleotide variation between these markerss and their association with the different DAZ genes. In brief, digestion of sY5877 with Dra1 produces four fragments of 122 base pairs, 73 base pairs, 49 basee pairs, and 26 base pairs in DAZ1 and DAZ2, which both contain the T variantt of this sequence tagged site. In DAZ3 and DAZ4, which contain the C variantt of sY587, three fragments of 195 base pairs, 49 base pairs, and 26 base pairss are detected. Similarly, digestion of sY581 with 5au3A produces a 189-base pairr fragment and a 63- base pair fragment in DAZ1 and DAZ4 and three fragmentss of 130 base pairs, 59 base pairs, and 63 base pairs in DAZ2 and DAZ3. Finally,, digestion of sY586 with Taq1 produces two fragments of 184 base pairs andd 117 base pairs in DAZ1, DAZ3, and DAZ4, whereas Y586 of DAZ2 remains undigested,, resulting in one 301-base pair fragment. Sequencee family variant PCR in sY587 distinguished cluster 1 and cluster 2, andd sequence family variant PCR in sY581 distinguished between left or right geness in both clusters. Fragment sizes of the PCR products after digestion with restrictionn enzymes are shown in Table 1. If incomplete DAZ signatures were detected,, tests were repeated. 69 9 Chapterr 4 FISH H Wee used three sequenced DAZ cosmids as probes for FISH (6). Cosmid 18E88 (Cenbank AC010089) encompasses the 5' end portions of two neighboring DAZDAZ genes (Fig. 1). Cosmid 63C9 (Genbank AC000021) contains exons 2 through 111 —almost an entire DAI gene. Cosmid 46A6 (Genbank AC000022) derives from thee 3' end portion of DAZ; it contains exons 8 through 11 and 35 kb downstream off the gene. Single-colorr FISH was performed on interphase nuclei from lymphocytes accordingg to standard procedures (1 2). Cosmid 1 8E8 was used to detect the presencee of the two DAZ clusters. Because the DAZ genes are located in two clusters,, each containing two DAZ genes in a head-to-head orientation, cosmid 18E88 shows predominantly one signal per cluster. Because superimposition of the twoo signals can lead to misinterpretation, at least 200 interphase nuclei were examinedd before the presence of one or two signals was accepted. Ann average of 20 patients was tested in every FISH procedure. Lymphocytes fromm a fertile donor were included in every FISH procedure as internal control on thee validity of the FISH procedure. The technician performing the counting of the signalss was not aware of the outcome of the PCR experiments. Extendedd chromatin fibers from lymphocytes were prepared by using SDS / ethylenediaminee tetraacetic acid extraction (1 3). Fiber FISH was performed by usingg a combination of probes 18E8 with 46A6 to detect the 5'- and 3' portions of thee DAZ genes and a combination of probes 18E8 with 63C9 to detect the 5' portionn and the body of the DAZ genes in single clusters.
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