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Biomedical subjects

P H Vogt

Publications and source records attributed to P H Vogt.

At least 19 recordsLinked to original sources
PubMed2006

Premature ovarian failure (POF) syndrome: towards the molecular clinical analysis of its genetic complexity.

The Premature Ovarian Failure (POF) syndrome is a very heterogeneous clinical disorder due probably to the complex genetic networks controlling human folliculogenesis. Clinical subgroups of POF patients whose aetiology of ovarian failure is based on the same genetic factors are therefore difficult to establish. Some experimental evidence suggests that these genes might be clustered on the female sex chromosome in the POF1 and POF2 loci. This review is aimed to present an overview of the actual structural changes of the X chromosome causing POF, and to present a number of X and autosomal female fertility genes which are probably key genes in human folliculogenesis and are therefore prominent POF candidate genes. Towards the molecular analysis of their functional contribution to the genetic aetiology of POF in the clinic, an interdisciplinary scheme for their diagnostic analysis is presented in a pilot study focussed on chromosome analyses and the expression analysis of some major POF candidate genes (DAZL, DBX, FOXL2, INHalpha, GDF9, USP9X) in the leukocytes of 101 POF patients. It starts with a comprehensive and significantly improved clinical diagnostic program for this large and heterogeneous patient group.

Animals↗
PubMed2004

The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control.

We explored the function of the human DEAD-box Y RNA helicase DBY (DDX3Y) gene located in the (AZFa) region on the human Y chromosome (Yq11.21). Deletion of this Y interval is known to be a major cause for the occurrence of a severe testicular pathology, the Sertoli-cell-only (SCO) syndrome. DBY has a structural homologue on the short arm of the X chromosome DBX (DDX3X) (Xp11.4). We found widespread transcription of both genes in each tissue analyzed, although predominantly in testis tissue. However, translation of DBY was detected only in the male germ line, whereas DBX protein was expressed in all tissues analyzed. In testis tissue sections, DBY protein was found predominantly in spermatogonia, whereas DBX protein was expressed after meiosis in spermatids. We conclude that although both RNA helicases are structurally very similar, they have diverged functionally to fulfill different roles in the RNA metabolism of human spermatogenesis, and that deletion of the DBY gene is the most likely cause of the severe testicular pathology observed in men with AZFa deletions.

Chromosomes, Human, Y↗
PubMed2004

Cytogenetic and molecular analysis of a family with three brothers afflicted with germ-cell cancer.

A thorough cytogenetic investigation and an analysis of detailed questionnaires were performed in a family with three brothers afflicted with germ-cell tumors (GCTs), in an attempt to detect a congenital factor related either to a hereditary genetic background or an environmental/lifestyle influence. One brother had an intracranial tumor in the pineal region and the two others had testicular tumors. Peripheral blood was studied by traditional karyotyping, multicolor-FISH, high-resolution comparative genomic hybridization (HR-CGH), and molecular analysis of selected loci on sex chromosomes (Yq11 region, TSPY, and the androgen receptor gene); however, no abnormalities were detected. The HR-CGH analysis of microdissected histological components of the overt tumors and the adjacent carcinoma in situ demonstrated a pattern of genomic imbalances characteristic for sporadic GCTs, including gain of 12p. The questionnaire and interview revealed a history of different cancers in the extended family, and a possible in utero and/or infantile exposure of the three brothers with GCTs to compounds suspected of endocrine-disrupting properties. Although no genetic aberration was detected in this family, we suspect the presence of a recessive hereditary factor pre-disposing to cancer, which probably was manifested as GCTs in the three brothers because of an adverse effect of an environmental factor on the early germ-cell differentiation.

Adult↗
PubMed2003

A large AZFc deletion removes DAZ3/DAZ4 and nearby genes from men in Y haplogroup N.

Deletion of the entire AZFc locus on the human Y chromosome leads to male infertility. The functional roles of the individual gene families mapped to AZFc are, however, still poorly understood, since the analysis of the region is complicated by its repeated structure. We have therefore used single-nucleotide variants (SNVs) across approximately 3 Mb of the AZFc sequence to identify 17 AZFc haplotypes and have examined them for deletion of individual AZFc gene copies. We found five individuals who lacked SNVs from a large segment of DNA containing the DAZ3/DAZ4 and BPY2.2/BPY2.3 gene doublets in distal AZFc. Southern blot analyses showed that the lack of these SNVs was due to deletion of the underlying DNA segment. Typing 118 binary Y markers showed that all five individuals belonged to Y haplogroup N, and 15 of 15 independently ascertained men in haplogroup N carried a similar deletion. Haplogroup N is known to be common and widespread in Europe and Asia, and there is no indication of reduced fertility in men with this Y chromosome. We therefore conclude that a common variant of the human Y chromosome lacks the DAZ3/DAZ4 and BPY2.2/BPY2.3 doublets in distal AZFc and thus that these genes cannot be required for male fertility; the gene content of the AZFc locus is likely to be genetically redundant. Furthermore, the observed deletions cannot be derived from the GenBank reference sequence by a single recombination event; an origin by homologous recombination from such a sequence organization must be preceded by an inversion event. These data confirm the expectation that the human Y chromosome sequence and gene complement may differ substantially between individuals and more variations are to be expected in different Y chromosomal haplogroups.

Chromosome Mapping↗
PubMed2002

High frequency of DAZ1/DAZ2 gene deletions in patients with severe oligozoospermia.

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.

Chromosomes, Artificial, Bacterial↗
PubMed2001

The shorter zinc finger protein ZNF230 gene message is transcribed in fertile male testes and may be related to human spermatogenesis.

The zinc finger gene family represents one of the largest in the mammalian genome, with several of these genes reported to be involved in spermatogenesis. A newly discovered gene has been identified that is expressed abundantly in the testicular tissue of fertile men as determined by mRNA differential display. The gene encodes a C(3)HC(4)-type zinc finger protein motif (ring finger motif) consistent with a role in pre-meiotic or post-meiotic sperm development. The gene was named ZNF230 and mapped to the short arm of chromosome 11 (11p15). ZNF230 has two transcripts, of 1 kb and 4.4 kb in length. The shorter 1 kb transcript was only detected in testicular tissue whereas the longer 4.4 kb transcript was not detected in testis but was found in several other tissues. The lack of detectable ZNF230 expression in azoospermic patients by reverse transcriptase-mediated PCR analysis is interpreted to mean that this gene is involved in maintaining normal human male fertility.

Amino Acid Sequence↗
PubMed2001

High deletion frequency of the complete AZFa sequence in men with Sertoli-cell-only syndrome.

We have developed a rapid screening protocol for deletion analysis of the complete AZFa sequence (i.e. 792 kb) on the Y chromosome of patients with idiopathic Sertoli-cell-only (SCO) syndrome. This Y deletion was mapped earlier in proximal Yq11 and first found in the Y chromosome of the SCO patient JOLAR, now designated as the AZFa reference patient. We now show that similar AZFa deletions occur with a frequency of 9% in the SCO patient group. In two multiplex polymerase chain reaction experiments, deletions of the complete AZFa sequence were identified by a typical deletion pattern of four new sequence-tagged sites (STS): AZFa-prox1, positive; AZFa-prox2, negative; AZFa-dist1, negative; AZFa-dist2, positive. The STS were established in the proximal and distal neighbourhoods of the two retroviral sequence blocks (HERV15yq1 and HERV15yq2) which encompass the break-point sites for AZFa deletions of the human Y chromosome. We have found deletions of the complete AZFa sequence always associated with a uniform SCO pattern on testicular biopsies. Patients with other testicular histologies as described in the literature and in this paper have only partial AZFa deletions. The current AZFa screening protocols can therefore be improved by analysing the extension of AZFa deletions. This may provide a valuable prognostic tool for infertility clinics performing testicular sperm extraction, as it would enable the exclusion of AZFa patients with a complete SCO syndrome.

Chromosomes, Artificial, Bacterial↗
PubMed2000

Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events.

We mapped the breakpoints of the AZoospermia factor a (AZFa) microdeletion located in proximal Yq11 in six men with complete germ cell aplasia, i.e. Sertoli Cell Only syndrome (SCO). The proximal breakpoints were identified in a long retroviral sequence block (HERV15yq1: 9747 nucleotides) at the 5' end of the DYS11 DNA locus in Yq11, interval D3. The distal breakpoints were found in a homologous HERV15 sequence block mapped to the Yq11 interval D6, i.e. in the distal part of the AZFa region (HERV15yq2: 9969 nucleotides). Compared with the HERV15yq1 sequence, HERV15yq2 is marked by a deletion of a HERV15 sequence domain at its 5' end and insertion of an LINE 1 3'-UTR sequence block (L1PA4) of similar length at its 3' end. The deletion of the L1PA4 element was recognized as the molecular origin of the DYS11 12f2 restriction fragment length polymorphism. For all six AZFa patients it was possible to perform PCR experiments bridging both retroviral sequence blocks, which map in a distance of 781.557 kb in proximal Yq11 in fertile men. The AZFa breakpoint-fusion regions were located in their recombined HERV15yq1/HERV15yq2 sequence blocks in either one of two long identical sequence domains (ID1 and ID2). We therefore assume that intrachromosomal recombination events between the two homologous retroviral sequence blocks in proximal Yq11 are probably the causative agents for most of the AZFa microdeletions observed in men with SCO syndrome. A mean value of 792 kb was estimated for their molecular lengths.

Endogenous Retroviruses↗
PubMed2000

Conservation of the deleted-in-azoospermia-like-1 (DAZL1) gene structure in old world monkeys points to a homologous function of DAZL1 in this primate class.

We isolated the complete deleted-in-azoospermia-like-1 (DAZL1) gene of the old world monkey Macaca fascicularis (tentatively designated as MafaDAZL1) and compared its sequence structure to that of the other DAZL1 genes isolated so far. In addition to the homologous RNA recognition motif (RRM domain), we only identified a high conservation of the Mafa-DAZL1 coding region to the mammalian DAZL1 genes (i.e. mouse: Dazl1; and human: DAZL1) and to that of Xenopus (xdazl). Only in the primates, Macaca fascicularis and human, sequences and lengths of the 5' and 3' untranslated DAZL1 gene structures (UTRs) displayed a similar conservation as their coding regions (i.e. 91-94%). Both belong to the primate class of old world monkeys evolutionarily separated 36-55 million years ago (1). The strong conservation of the complete DAZL1 gene structure in both primate species suggests a similar control and maturation pathway of DAZL1 transcripts in the germ line of old world monkeys and also indicates a homologous function of the DAZL1 RNA-binding protein in this primate class.

3' Untranslated Regions↗
PubMed2000

Y-chromosomal DNA haplotypes in infertile European males carrying Y-microdeletions.

We have determined Y-chromosomal DNA haplotypes in 73 infertile European males carrying Y microdeletions and compared them with the haplotypes of 299 infertile males lacking microdeletions. Chromosomes were typed with a set of 11 binary Y markers, which identified 8 haplogroups in the sample. Haplogroup frequencies were compared between 3 microdeletion classes and the non-deleted infertile males. Deletions arise on many different haplotypic backgrounds. No statistically significant differences in frequency were seen, although the small number of AZFa deletions lay predominantly on one branch of the Y haplotype tree.

DNA↗
PubMed2000

Arylsulfatase D gene in Xp22.3 encodes two protein isoforms.

The human genome contains six arylsulfatase genes (ARSA-ARSF), of which four are clustered in a distal region of the short arm of the X chromosome (Xp22.3). They were probably generated by a series of evolutionary duplication events; their exon-intron boundaries are identical. Nevertheless, different transcript lengths and the absence of cross-hybridizations point to a specific function of each gene in human cell metabolism, and multiple transcripts suggest the coding of protein isoforms. We identified a novel protein isoform of the ARSD gene by isolation of a series of cDNA clones from a human testis cDNA library. The clones were only partially identical to another series of ARSD clones isolated earlier (now designated ARSDalpha clones). Their specific C-terminal region (1160 nt) encodes a novel ARSD peptide of 48 amino acids and was identified as part of intron 6 of the ARSD gene in Xp22.3. We therefore designate them ARSDbeta clones. Expression analyses of ARSDalpha and ARSDbeta by semiquantitative RT-PCR revealed the presence of both in multiple human tissues, although in different quantities. A physiologic substrate for arylsulfatase D proteins is not known. We therefore estimated their sulfatase activities in vitro with the aid of the 4-methylumbelliferyl sulfate (4-MUS) assay. Surprisingly, neither ARSD protein isoform demonstrated any sulfatase activity alone or in combination, although their catalytic peptide domain is strongly conserved in comparison with that of the other X-chromosomal arylsulfatase enzymes (ARSC, ARSE, ARSF), all of which are functionally active in the 4-MUS assay.

Amino Acid Sequence↗
PubMed1998

DAZ (Deleted in AZoospermia) genes encode proteins located in human late spermatids and in sperm tails.

We analysed the location of proteins encoded by the DAZ (Deleted in AZoospermia) genes in human testis tissue and in mature spermatozoa. The DAZ genes are known to be expressed exclusively in the human male germ line, and are candidate genes for the expression of the azoospermia factor AZFc mapped recently to distal Yq11. They encode testis-specific RNA binding proteins, the function of which is not yet known. Immunostaining experiments with antibodies prepared for the specific peptide domain encoded by the DAZ2 transcript (formerly SPGY1) revealed the presence of DAZ proteins in the innermost layer of the male germ cell epithelium and in the tails of spermatozoa. This suggests a function for DAZ proteins in the RNA metabolism of late spermatids, presumably in the storage or transport of testis-specific mRNA, the translation of which is repressed until the formation of mature spermatozoa. Deletion of DAZ genes is supposed not to interfere with human sperm maturation but to result in a gradual reduction of mature spermatozoa.

Amino Acid Sequence↗
PubMed1998

Human chromosome deletions in Yq11, AZF candidate genes and male infertility: history and update.

Human chromosome deletions in Yq11 seem to occur frequently as de novo mutation events in men with idiopathic azoospermia or severe oligozoospermia. However, the molecular extensions of these deletions are variable. They can be large and therefore visible under the microscope or small, not visible under the microscope, and containing the deletion of one or more DNA loci recently mapped in an apparently consecutive order along the Yq11 chromosome region. The results of 20 extensive microdeletion screening programmes have now corroborated the prevalence of the deletion of three non-overlapping DNA regions in proximal, middle and distal Yq11, which were designated earlier as AZFa, AZFb and AZFc. Deletions of single DNA loci were also reported, but as de novo and as polymorphic mutation events. Their clinical significance with regard to the men's infertility should therefore initially be handled with caution. Multiple Y genes expressed in human testis have now been mapped to each AZF region. At least one of them should be functional in human spermatogenesis and, if mutated, cause azoospermia. However, gene-specific mutations leading to the azoospermia phenotype have not yet been found for any of these AZF candidate genes. This might raise the question as to whether an AZF gene really exists in Yq11 or if the azoospermia phenotypes are only observed after deletion of a complete AZF region, after deletion of its complete gene content.

Biological Factors↗
PubMed1997

Expression of RBM in the nuclei of human germ cells is dependent on a critical region of the Y chromosome long arm.

The association of abnormal spermatogenesis in men with Y chromosome deletions suggests that genes important for spermatogenesis have been removed from these individuals. Recently, genes encoding two putative RNA-binding proteins (RBM and DAZ/SPGY) have been mapped to two different regions of the human Y chromosome. Both of these genes encode proteins that contain a single RNA recognition motif and a (different) internally repeating sequence. Y-linked RBM homologues are found in all mammalian species. We have raised an antiserum to RBM and used it to show that RBM is a nuclear protein expressed in fetal, prepubertal, and adult male germ cells. The distribution of RBM protein in the adult correlates with the pattern of transcriptional activity in spermatogenesis, suggesting that RBM is involved in the nuclear metabolism of newly synthesized RNA. RBM sequences are found on both arms of the Y chromosome making genotype-phenotype correlations difficult for this gene family. To address the location of the functional genes and the consequences of their deletion, we examined a panel of men with Y chromosome deletions and known testicular pathologies using this antiserum. This approach enabled us to map a region of the Y chromosome essential for RBM expression. In the absence of detectable RBM expression we see stages of germ cell development up to early meiosis, but not past this point into the haploid phase of spermatogenesis.

Adult↗
PubMed1997

Human Y chromosome deletions in Yq11 and male fertility.

An overview is given about the current knowledge and research activities on the molecular analysis of interstitial deletions in the euchromatic part of the long arm of the human Y chromosome (Yq11). These mutations are associated with the male specific phenotype of azoospermia and severe oligozoospermia. The fact is stressed that only "de novo" microdeletions in Yq11 are of any diagnostic value in the infertility clinic because numerous polymorphic deletion events in Yq11 have also been reported. Three different "de novo" Yq11 microdeletions associated with male infertility are now found repeatedly (31 cases) in more than 700 patients. They strongly support the presence of at least three spermatogenesis loci in Yq11. They have been designated as AZFa, AZFb, and AZFc. Each of them should contain at least one Y gene functional in spermatogenesis and, if mutated, it should induce the same sterile phenotype as the corresponding AZF locus. These genes have not yet been found. However, some candidate genes exist: RBM for AZFb. DAZ and SPGY for AZFc. It is remarkable that all three encode testis specific RNA binding proteins with a similar sequence structure. Their structure and potential relationship is disussed.

Base Sequence↗
PubMed1997

Genetics of idiopathic male infertility: Y chromosomal azoospermia factors (AZFa, AZFb, AZFc).

Y chromosomal spermatogenesis loci in Yq11 are disrupted with a frequency of 5-20% in men suffering from idiopathic infertility (azoospermia or severe oligozoospermia). They were designated azoospermia factors (AZFa, AZFb, AZFc). An efficient schedule for their molecular diagnosis in each infertility clinic is presented. In addition, I will include our current knowledge about their biological function during human germ cell development and a description of their pathology in men suffering from deletion of one or more AZF loci. Each Y gene expressed in testis tissue and located in Yq11, in a position overlapping one of the AZF loci, is an AZF candidate gene. Their diagnostic analysis will be described in a separate section. The clinical diagnosis of AZF candidate genes cannot substitute for diagnosis of the genetically defined AZF loci. Therefore, analysis of candidate genes is aimed at answering the question of whether mutations in their exon structures are able to induce the same pathological phenotypes as deletion of the corresponding AZF locus. Only after these gene mutations have been analysed can the AZF candidate gene be designated as a real AZF gene. Therefore, the basic aim of our current research is isolation and identification of all AZF genes.

Base Sequence↗