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Query: UNIPROT:P06889 (Mol)
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De-novo deletions involving AZFa, b, c and d are one of the most common chromosomal aberrations in man resulting in defective spermatogenesis and male infertility. Currently, Yq deletion screening involves either single or multiplex PCR using Y-specific sequence tagged site markers and the subsequent analysis of the amplification products on ethidium bromide-stained agarose gels. To improve the practicality of routine and high throughput Yq testing, we have developed a more sensitive multiplex fluorescent (FL)-PCR screening system using genomic DNA extracted from cheek buccal cells as a readily available PCR template. For genetic follow-up studies of ICSI-conceived children, we also developed a DNA fingerprinting system based on the co-amplification of four highly polymorphic markers to validate family samples and detect any potential extraneous DNA contamination that could cause a misdiagnosis. Multiplex FL-PCR analysis of buccal cell DNA from two infertile men who conceived three sons by ICSI demonstrated that their Yq deletions were vertically transmitted. Fine mapping with additional Yq markers revealed identical deletion endpoints involving the loss of AZFdc sequences. This firstly indicates that the extent of the Yq deletion was unchanged on ICSI transmission and secondly supports the view that AZFdc deletions may arise by a common de-novo event. Analysis of paternal, maternal and sibling DNA fingerprints showed the co-inheritance of parental alleles by each male child and confirmed the expected relationship between each family member. The application of these new FL-PCR based screening tests in genetic follow-up studies will assist in confirming transmission of specific genetic defects to male offspring conceived by ICSI and provide a basis for genetic counselling and potential treatment options as these boys approach sexual maturity.
Mol Hum Reprod 2002 Jun
PMID:Genetic follow-up of male offspring born by ICSI, using a multiplex fluorescent PCR-based test for Yq deletions. 1202 79

In mice carrying the autosomal recessive mutation 'abnormal spermatozoon head shape' (azh) all spermatozoa display a highly abnormal head morphology that differs drastically from the compact and hook-shaped head of the normal murine sperm. Moreover, the azh mutation causes tail abnormalities often resulting in coiled sperm tails or in the decapitation of the sperm head from the flagellum. We have isolated and characterized murine Hook1 cDNA and analyzed the corresponding genomic structure. Furthermore, the Hook1 gene was mapped to the same region on chromosome 4 to which the azh locus was previously linked. The Hook1 gene is predominantly expressed in haploid male germ cells, and immunohistochemical analysis revealed that Hook1 is responsible for the linkage of the microtubular manchette and the flagellum to cellular structures. Here, we report that the azh mutation is due to a deletion of exons 10 and 11 in the murine Hook1 gene leading to a non-functional protein. Our results indicate that loss of Hook1 function results in ectopic positioning of microtubular structures within the spermatid and causes the azh phenotype. Therefore, the human HOOK1 gene could serve as a candidate gene for male infertility due to teratozoospermia or decapitation defects.
Hum Mol Genet 2002 Jul 01
PMID:The Hook1 gene is non-functional in the abnormal spermatozoon head shape (azh) mutant mouse. 1207 9

Approaches to study human epididymal functions are limited. Therefore, suitable animal models are highly desirable, yet difficult to find among the few species studied on a molecular level to date. This review summarizes our progress in the development of the canine epididymis as an alternative model. Dogs are biomedically a key species because they are subject to many of the same diseases as humans and already serve as a model for a number of human pathologies, including genetic diseases. It is thus consistent that an appraisal of epididymal specific gene expression has been started in the dog, including the molecular cloning and characterization of canine epididymal proteins. These proteins, in addition to a high overall sequence similarity to the human, show a similar tissue distribution, relative abundance and spatial pattern within the epididymis. Moreover, the dog epididymis offers an excellent source for cell culture studies, and immortalization of the canine epididymal duct epithelium has been achieved, encouraging regulatory studies of epididymal gene expression in vitro. Thus, the dog already fulfils many of the criteria of a good model of the human epididymis on a molecular level. Further progress may be expected with the advance of the canine genome project. If there is a genetic basis for male infertility, then the dog provides the advantage of the exploitation of a species that combines a maximum of genetic variation within a species with the capacity to minimize that variation within a defined pedigree.
Mol Hum Reprod 2002 Aug
PMID:The dog as a model to study human epididymal function at a molecular level. 1214 99

Aberrant reorganization of hippocampal mossy fibers occurs in human temporal lobe epilepsy and rodent epilepsy models. We generated a mouse model showing massive late-onset aberrant mossy fiber sprouting in the adult hippocampus. The mutation in this mouse model derives from an intronic insertion of transgene DNA in the mouse PLC-beta1 gene (PLC-beta 1(-/-)(TC) mutation) leading to a splice mutation of the PLC-beta 1 gene and a complete loss of downstream PLC-beta 1 expression. PLC-beta 1(-/-)(TC) mutants develop a loss of NMDA-receptors in the stratum oriens of region CA1, apoptotic neuronal death, and reduced hippocampal PKC activity. The phenotype of these mice further consists of a late-onset epileptiform hyperexcitability, behavioral modifications in a radial maze and in an open field, female nurturing defect, and male infertility. In the present study, we provide evidence that the arising of the behavioral phenotype in PLC-beta 1(-/-)(TC) mice correlates in time with the development of the aberrant mossy fiber projections and that the disruption of the PLC-beta 1-mediated signal transduction pathway may lead to a functional cholinergic denervation, which could cause hippocampal remodeling and, in consequence, epileptiform hyperexcitability.
Mol Cell Neurosci 2002 Dec
PMID:Disruption of PLC-beta 1-mediated signal transduction in mutant mice causes age-dependent hippocampal mossy fiber sprouting and neurodegeneration. 1250 92

Deletions of the AZFa region on the long arm of the human Y chromosome cause male infertility. Previous work has shown that this is an example of a genomic disorder, since most deletions are caused by non-allelic homologous recombination between endogenous retroviral elements (HERVs) flanking the 780 kb region. The reciprocal products of these deletion events, AZFa duplications, have not been reported to date. Here we show that duplication chromosomes exist in population samples by detecting Y-chromosomal short tandem repeat (YSTR) allele duplications within the AZFa region, and by showing that two chromosomes carrying these duplicated alleles contain a third junction-specific HERV sequence. Sequence analysis of these cases, which most likely represent independent duplication events, shows that breakpoints lie in the same region of inter-HERV sequence identity as do deletion breakpoints, and thus that the mechanism of duplication is indeed the reciprocal of deletion. Consideration of the accumulated Y-STR allele diversity between duplicated copies of the AZFa region indicates that one of the duplication chromosomes has been in the population for at least 17 generations, and therefore must be compatible with male fertility.
Hum Mol Genet 2003 Feb 01
PMID:Duplications of the AZFa region of the human Y chromosome are mediated by homologous recombination between HERVs and are compatible with male fertility. 1255 87

The ubiquitin-conjugating enzymes HR6A and HR6B are the two mammalian homologs of Saccharomyces cerevisiae RAD6. In yeast, RAD6 plays an important role in postreplication DNA repair and in sporulation. HR6B knockout mice are viable, but spermatogenesis is markedly affected during postmeiotic steps, leading to male infertility. In the present study, increased apoptosis of HR6B knockout primary spermatocytes was detected during the first wave of spermatogenesis, indicating that HR6B performs a primary role during the meiotic prophase. Detailed analysis of HR6B knockout pachytene nuclei showed major changes in the synaptonemal complexes. These complexes were found to be longer. In addition, we often found depletion of synaptonemal complex proteins from near telomeric regions in the HR6B knockout pachytene nuclei. Finally, we detected an increased number of foci containing the mismatch DNA repair protein MLH1 in these nuclei, reflecting a remarkable and consistent increase (20 to 25%) in crossing-over frequency. The present findings reveal a specific requirement for the ubiquitin-conjugating activity of HR6B in relation to dynamic aspects of the synaptonemal complex and meiotic recombination in spermatocytes.
Mol Cell Biol 2003 Feb
PMID:Loss of HR6B ubiquitin-conjugating activity results in damaged synaptonemal complex structure and increased crossing-over frequency during the male meiotic prophase. 1255 76

Although various genetic factors have been implicated in human male infertility, the causative genes for the different types of idiopathic male infertility have not been elucidated. Protamines, which are the major DNA-binding proteins in the sperm nucleus, package the DNA into the sperm head. Analysis of the human protamine-1 (PRM1) and -2 (PRM2) gene sequences in 226 sterile male patients and in 270 proven-fertile male volunteers revealed four single nucleotide polymorphisms (SNPs) in the PRM1 coding region, which did not cause any amino acid substitutions, and one SNP in the PRM2 gene, which produced translation termination. We also observed one SNP in the 3' non-coding region of the PRM1 gene, and two SNPs within the intron of the PRM2 gene. The prevalence of these SNPs was similar in both infertile patients and in proven-fertile volunteers, except that the c248t alteration in the PRM2 gene induced a nonsense codon under conditions of heterozygosity in one infertile patient. Although the PRM1 and PRM2 genes are highly conserved, the single SNP in the PRM2 gene that induces translation termination may result in male infertility due to haploinsufficiency of PRM2.
Mol Hum Reprod 2003 Feb
PMID:Single nucleotide polymorphisms in the protamine-1 and -2 genes of fertile and infertile human male populations. 1256 75

Semenogelin (Sg) is the major protein involved in gelatinous entrapment of ejaculated spermatozoa, which plays an important role on the regulation of sperm motility and fertilization. We investigated deletion in Sg-I and -II genomic genes with the objective of diagnosis of asthenozoospermia. As a result, heterozygous deletion of a repeat site in exon 2 of the Sg-I genomic gene was identified. The repeat site-deleted Sg-I protein was also detected together with full-sized Sg-I in semen ejaculated from infertile patients who were diagnosed as having the heterozygous deletion of a repeat site in exon 2 of the Sg-I genomic gene. However, the deletion was found not only in male infertile patients but also in fertile men. The deletion frequency was 1.1% in infertile patients and 2.8% in fertile men. The deletion was found to have no effect on testicular volume, endocrine hormone concentration and sperm quality. In addition, the wild-type, the repeat site-deleted and active site-deleted Sg-I proteins were produced in recombinant baculovirus-infected Sf21 cells and their seminal plasma motility inhibitor (SPMI) activities were determined. The repeat site-deleted Sg-I had similar SPMI activity to the full-sized Sg-I, while the active site-deleted Sg-I had almost lost SPMI activity. In conclusion, the deletion of a repeat site in the Sg-I genomic gene found in infertile patients and fertile men does not affect sperm quality and male infertility.
Int J Mol Med 2003 Apr
PMID:A large deletion of the repeat site in semenogelin I is not involved in male infertility. 1263 94

About 30% of couple infertilities are of male origin, some of them caused by genetic abnormalities of the Y chromosome. Deletions in AZF region can cause severe spermatogenic defects ranging from non-obstructive azoospermia to oligospermia. The intracytoplasmatic sperm injection technique (ICSI) is rapidly becoming a versatile procedure for human assisted reproduction in case of male infertility. The use of ICSI allows Y chromosome defects to be passed from father. The goal of our study is to evaluate the frequency of microdeletions in the long arm of Y chromosome, within the AZF regions, in these cases of infertilities, using molecular genetics techniques. Thirty infertile men with azoospermia or oligozoospermia, determined by spermogram, were studied after exclusion of patients with endocrine or obstructive causes of infertility. Peripheral blood DNA was extracted from each patient, then amplified by multiplex PCR with STS genomic markers from the Y chromosome AZF zones. Each case was checked by multiplex PCR through coamplification with the SRY marker. Three men with microdeletions of the long arm of the Y chromosome were diagnosed among the 30 patients, corresponding to a proportion of 10%. The relatively high proportion of microdeletions found in our population suggest the need for strict patient selection to avoid unnecessary screening for long arm Y chromosome microdeletions. The molecular diagnostics was performed according to the current European Academy of Andrology laboratory guidelines for molecular diagnosis of Y chromosomal microdeletions.
J Cell Mol Med
PMID:Screening for microdeletions in human Y chromosome--AZF candidate genes and male infertility. 1276 60

Infertile men exhibit an aberrant protamine-1 (Prm1) to protamine-2 (Prm2) ratio at both the mRNA and protein level. We therefore investigated whether male infertility could be related to the amount of Prm1 and Prm2 mRNA by applying real time quantitative PCR following RNA extraction from routinely Bouin-fixed and paraffin-embedded testicular biopsies. Samples (n = 51) were normalized to the same amount and similar size of tissue sections. The threshold cycle (C(T)) representing a measure of the initial number of mRNA copies was significantly (P < 0.001) higher for Prm1, but not Prm2, and thus the amount of Prm1 mRNA was lower in men with at least qualitatively normal spermatogenesis (Prm1: 29.88 +/- 2.99; Prm2: 34.28 +/- 2.26) and impaired spermatogenesis (Prm1: 31.89 +/- 2.54; Prm2: 35.59 +/- 2.09) compared with men with obstructive azoospermia and quantitatively normal spermatogenesis (Prm1: 29.04 +/- 1.02; Prm2: 34.91 +/- 1.40). In addition, the Prm1 - Prm2 C(T) difference (deltaC(T)) was significantly (P < 0.001) decreased in these two groups. A negative correlation (r = -0.504; P < 0.001) was demonstrated between the score for efficiency of spermatogenesis and the C(T) for Prm1. These data suggest that the decreasing amount of Prm1 and, as a consequence, the aberrant Prm1:Prm2 mRNA ratio plays an important role for male infertility and may serve as a possible predictive factor for the outcome of ICSI.
Mol Hum Reprod 2003 Jun
PMID:Decreased protamine-1 transcript levels in testes from infertile men. 1277 Dec 33


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