Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021359 (infertility)
 26,075 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the cystic fibrosis (CF) conductance transmembrane regulator (CFTR) gene have been detected in patients with CF and in males with infertility attributable to congenital bilateral absence of the vas deferens (CBAVD). Thirty individuals with CBAVD and 10 with congenital unilateral absence of the vas deferens (CUAVD) were analyzed by single-strand conformation analysis and denaturing gradient gel electrophoresis for mutations in most of the CFTR gene. All 40 individuals were pancreatic sufficient, but twenty patients had recurrent or sporadic respiratory infections, asthma/asthmatic bronchitis, and/or rhino-sinusitis. Agenesia or displasia of one or both seminal vesicles was detected in 30 men and other urogenital malformations were present in six subjects. Among the 40 samples, we identified 13 different CFTR mutations, two of which were previously unknown. One new mutation in exon 4 was the deletion of glutamic acid at codon 115 (delta E115). A second new mutation was found in exon 17b, viz., an A --> C substitution at position 3311, changing lysine to threonine at codon 1060 (K1060T). CFTR mutations were detected in 22 out of 30 (73.3%) CBAVD patients and in one out of 10 (10%) CUAVD individuals, showing a significantly lower incidence of CFTR mutations in CBAVD/CUAVD patients (P << 0.0001), compared with that found in the CF patient population. Only three CBAVD patients were found with more than one CFTR mutation (delta F508/L206W, delta F508/R74W + D1270N, R117H/712-1G --> T), highlighting L206W, R74W/D1270N, and R117H as benign CF mutations. Sweat electrolyte values were increased in 76.6% of CBAVD patients, but three individuals without CFTR mutations had normal sweat electrolyte levels (10% of the total CBAVD patients), suggesting that factors other than CFTR mutations are involved in CBAVD. The failure to identify a second mutation in exons and their flanking regions of the CFTR gene suggests that these mutations could be located in introns or in the promoter region of CFTR. Such mutations could result in CFTR levels below the minimum 6%-10% necessary for normal protein function.
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PMID:Extensive analysis of 40 infertile patients with congenital absence of the vas deferens: in 50% of cases only one CFTR allele could be detected. 753 50

Activin is an important molecule that regulates hormonogenesis, cellular homeostasis (divide or die pathways), and differentiation programs (developmentally and in adult cells). The cellular mechanisms that integrate an activin signal into a physiological response include a binary receptor complex and tandem serine threonine kinases, intracellular signal mediators, and nuclear transcription factors. Activin antagonists (inhibins) and bioneutralizing binding proteins (follistatins) act as gating molecules to ensure accurate delivery of activin signals to cellular machinery. Correct execution of an activin cue intracellularly permits actions as fundamental as embryonic mesoderm development, neuronal survival, hematopoietic function, and reproductive cyclicity. Absent or incorrect activin signaling results in phenotypes as catastrophic as embryonic lethality, tumor formation, and infertility. The general ways in which a cell senses and responds to an activin signal will be reviewed in the first part of this paper. The role of this ligand in reproductive function will also be examined as a specific example of activin activity.
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PMID:Regulation of cellular and system function by activin. 960 19

Mutations in gonadotropin genes are extremely rare. Only one case of inactivating human luteinizing hormone (LH) beta mutation exists in the literature, a male with absence of Leydig cells, lack of spontaneous puberty and infertility. A total of four cases of inactivating mutation of the follicle-stimulating hormone beta (FSHbeta) gene (two female and two male) are known. The phenotype of the women was primary amenorrhea and absence of follicular maturation, the men were azoospermic. In addition, a common genetic variant (v) of LH was recently discovered. It is caused by two point mutations in the LH beta-subunit gene, resulting in amino acid alterations: Trp8 --> Arg and Ile15 --> Thr. In addition, the latter change introduces an extra glycosylation signal for oligosaccharide attachment to Asn13. The v-LHbeta allele has a carrier frequency ranging from 0 to > 50% in various populations. The variant LH molecule has increased intrinsic bioactivity in vitro, but decreased circulatory half-life in vivo, and the v-LHbeta promoter is about 50% more active in cell line transfections than that of wild-type (wt) LH. These differences in LH synthesis and action in individuals homo- or heterozygous for the v-LH allele are reflected by altered disposition to pathologies of pituitary-gonadal function, such as delayed puberty, polycystic ovarian syndrome and infertility.
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PMID:Mutations and polymorphisms in gonadotropin genes. 1041 23

Some pathologies of the pituitary-gonadal function have recently been found to be due to mutations of the gonadotropin or gonadotropin receptor genes. Although these conditions are extremely rare, they are very informative, by elucidating some less well characterized facets of normal gonadotropin function and the molecular pathogenesis of disturbances in sexual differentiation and fertility. In contrast, there is a common polymorphism in the Luteinizing Hormone (LH) beta-subunit gene, where two point mutations cause two alterations in the amino acid sequence (Trp8 --> Arg and Ile15 --> Thr) and introduce an extra glycosylation signal to Asn13. The carriers of this variant gene are largely healthy, but certain mild differences in their gonadal function have been found, as reflected by alterations in gonadal steroidogenesis, pubertal development and predisposition to diseases such as infertility, polycystic ovarian syndrome, and breast and prostatic cancer. The purpose of this chapter is to review the current knowledge of the occurrence, special functional features and clinical correlates of this LH variant.
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PMID:Alterations in gonadal steroidogenesis in individuals expressing a common genetic variant of luteinizing hormone. 1041 3

The incidence of impaired testicular descent (cryptorchidism) is high; 1-2% of boys at the age of 3 mo are diagnosed for this condition in western countries. Recent data on mice with targeted disruption of the Insl3/relaxin-like factor (RLF) gene proposed that this factor plays a role in testicular descent in fetal life. Male RLF-/- mice exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, associated with abnormal spermatogenesis and infertility. In the present study, we have sequenced the promoter region and both exons of the RLF gene in a cohort of 30 boys, seven of whom presented with a possible familial form of cryptorchidism and 23 with sporadic cryptorchidism. One of the nucleotide substitutions detected, G to A at position 178, predicted amino acid change. The mutation was localized to the C-peptide region, resulting in an alanine to threonine change and therefore classified as a conservative mutation. Four of the 30 cases analyzed were homozygous (13%), and 15 were heterozygous for the mutation (50%). However, the same mutation was also found in a control group of 89 men; 10% of them were homozygous, and 39% were heterozygous. Our results indicate that mutations in the RLF gene are not a common reason for cryptorchidism and that the common G178A polymorphism has no apparent relationship with this condition.
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PMID:A common polymorphism in the human relaxin-like factor (RLF) gene: no relationship with cryptorchidism. 1075 63

In a woman with infertility and an endometrial polyp, we analyzed the nucleotide sequence of the beta-subunit of her luteinizing hormone which showed anomalous immunogenecity in that it was recognized by time resolved-fluoroimmunoassay but not by immunoradiometric assay. The sequence analysis showed two substitutional mutations of beta-subunit Trp (TGG) to Arg (CGG) and Ile (ATC) to Thr (ACC). The variant luteinizing hormone might have had some relation to the infertility and the endometrial polyp. been described [2, 4, 13-15]. Although the role of the variant LH is still unclear, it has different biologicl activity as compared to normal LH and may play a role in causing infertility, menstrual disorder, endometriosis and spontaneous miscarriage [1, 3, 4, 9, 10, 17]. We now report a study of the DNA sequence of beta-subunit of anomalous LH in an infertile patient with an endometrial polyp.
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PMID:Genetic analysis of a variant luteinizing hormone in an infertile woman. 1156 44

Phospholipid hydroperoxide glutathione peroxidase (PHGPx), the product of gpx-4, is the major selenoprotein in sperm and is considered essential for fertilization because of its multiple roles in spermatogenesis, such as hydroperoxide detoxification, formation of the mitochondrial capsule, and chromatin condensation. Genomic DNA sequences of 3.148 kilobases covering the whole gpx-4 and its flanking regions were amplified from 63 men using the polymerase chain reaction and were analyzed for polymorphisms by direct sequencing. A total of 23 variant sites were detected; 2 were present only in control men (proven fathers; n = 21) and 10 were common to fertile controls and infertile patients (n = 42). A further 11 variant sites were seen in five of the infertile men only. Four of the gpx-4 variants were considered irrelevant to GPx-4-related fertility problems because they occurred homozygously in controls. The majority of the remaining variant sites are also of questionable relevance because they are located in introns or, as third base exchanges, do not affect the protein sequence. However, one of the exon variations leads to an Ala93-Thr exchange that reduces activity in a porcine GPx-4 homologue. Two detected promoter variations were shown by reporter gene constructs to affect transcription in somatic cell lines. These results indicate that gpx-4 polymorphism cannot generally account for the correlation of PHGPx content of sperm and fertility-related parameters, but further examination of this gene as a potential cause of infertility in particular cases is warranted.
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PMID:Genetic variations of gpx-4 and male infertility in humans. 1260 44

Inactivating mutations of the FSH receptor have been described in rare cases of premature ovarian failure. Only one mutation was associated with a complete phenotype, including delayed puberty, primary amenorrhea, and small ovaries. We describe here a new patient presenting a similar complete phenotype of premature ovarian failure, with high plasma FSH levels associated with very low estrogen and inhibin B levels. No biological response to high doses of recombinant FSH was detected. A novel homozygous Pro(519)Thr mutation was found in this patient. This mutation is located in the second extracellular loop of the FSH receptor, within a motif highly conserved in gonadotropin and TSH receptors. The mutation totally impairs adenylate cyclase stimulation in vitro. FSH binding experiments and confocal microscopy showed that this mutation alters the cell surface targeting of the mutated receptor, which remains trapped intracellularly. Histological studies of the ovaries of the patient showed an increase in the density of small follicles compared with age-matched normal women. A complete block in follicular maturation after the primary stage was also observed. Immunocytochemical studies allowed detection of the expression of c-Kit and proliferation cellular nuclear antigen, whereas no apoptosis was shown by the 3'-end-labeling method. This observation supports the concept that in humans FSH seems mandatory for the initiation of follicular growth only after the primary stage. In our patient complete FSH resistance yields infertility, which is remarkably associated with the persistence of a high number of small follicles.
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PMID:Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies. 1291 23

Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by lupus-like erythematous facial telangiectasia, sun sensitivity, infertility, stunted growth and a high predisposition to various types of cancer. Chromosomal abnormalities are hallmarks of this disorder, and high frequencies of sister chromatid exchanges and quadriradial configurations in lymphocytes and fibroblasts are diagnostic features. BLM is the causative gene for BS. We investigated the mutation in the BLM gene in 4 Japanese BS kindreds. Taken together with previously documented mutations, 2 kindreds were homozygous for 631delCAA and 2 were compound heterozygous for 631delCAA. The silent mutation of A1055C (Thr to Thr) was detected in control Japanese individuals. The 6-bp deletion/7-bp insertion at position 2,281, which most Askenazi Jewish BS patients carry, was not detected in 200 Japanese alleles. These results suggest that 631delCAA is a relatively common mutation among the Japanese BS patients.
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PMID:Relatively common mutations of the Bloom syndrome gene in the Japanese population. 1528 97

Follicle-stimulating hormone (FSH) is a key factor in human reproduction. FSH activates its receptor (FSHR) located exclusively on Sertoli cells in the testis and granulosa cells in the ovary. Two common single nucleotide polymorphisms (SNP) within exon 10 of the human FSHR gene result in two almost equally common allelic variants exhibiting threonine (Thr) or alanine (Ala) at position 307 in the hinge region, respectively, asparagine (Asn) or serine (Ser) at codon 680 of the intracellular domain. Clinical studies have demonstrated that p.N680S polymorphism determines the ovarian response to FSH stimulation in patients undergoing IVF-treatment. Patients with the Ser(680) allele need more FSH during the stimulation phase to reach the serum estradiol levels of Asn(680) patients. A study investigating women with normal, mono-ovulatory menstrual cycles revealed that the Ser(680)/Ser(680) genotype leads to higher FSH serum levels and a prolonged cycle. To date, the molecular mechanism underlying the partial "resistance" of the Ser(680)-FSHR to FSH remains unclear. Future experiments should extend our current understanding of FSH action on follicular selection and dominance, thereby permitting novel, patient-tailored therapies for infertility and fertility preservation.
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PMID:Polymorphism of the FSH receptor and ovarian response to FSH. 1754 58


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