Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sex chromosome disomy and diploidy rates on ejaculated spermatozoa from two patients with mosaic Klinefelter's syndrome were estimated, using X/Y/15 multicolour fluorescence in-situ hybridization (FISH). A 8/18 dual fluorescence in-situ hybridization analysis was also carried out. In triple FISH, a total of 1691 (patient 1) and 811 (patient 2) spermatozoa were analysed. Frequencies of cells with hyperhaploidies for sex chromosomes were 2. 01% and 3.45% for patients 1 and 2 respectively, with both patients showing a significantly increased incidence of 24,XY and 24,XX disomies and only patient 2 showing a significantly increased incidence of 24,YY disomy in comparison to the control (P < 0.001). The 46,XX diploidy rate in patient 1 was also significantly higher than the control (P < 0.01). The ratio of X-bearing to Y-bearing spermatozoa differed from the expected 1:1 ratio for only patient 1 (1.18:1). There was no significant difference for chromosomes 8, 15 or 18 disomy frequencies in comparison to those estimated in the control population. These results support the hypothesis that some 47,XXY cells are able to go through meiosis and form spermatozoa with an abnormal gonosomal complement. Thus, there is an increased risk, for these 46,XY/47,XXY men, of producing offspring with a gonosomal abnormality.
Mol Hum Reprod 2000 Jun
PMID:Segregation of sex chromosomes in spermatozoa of 46,XY/47,XXY men by multicolour fluorescence in-situ hybridization. 1082 76

The DAX-1 (NR0B1) gene encodes an unusual member of the nuclear hormone receptor superfamily which acts as a transcriptional repressor. Mutations in the human DAX-1 gene cause X-linked adrenal hypoplasia congenita (AHC) associated with hypogonadotropic hypogonadism (HHG). We have studied the intracellular localization of the DAX-1 protein in human adrenal cortex and mouse Leydig tumor cells and found it to be both nuclear and cytoplasmic. A significant proportion of DAX-1 is associated with polyribosomes and is found complexed with polyadenylated RNA. DAX-1 directly binds to RNA, two domains within the protein being responsible for cooperative binding activity and specificity. Mutations in DAX-1 found in AHC-HHG patients significantly impair RNA binding. These findings reveal that DAX-1 plays multiple regulatory roles at the transcriptional and posttranscriptional levels.
Mol Cell Biol 2000 Jul
PMID:Orphan receptor DAX-1 is a shuttling RNA binding protein associated with polyribosomes via mRNA. 1084 16

The objective of this study was to elucidate the cause of the spermatogenic defect in idiopathic azoospermia and non-mosaic type of Klinefelter syndrome. Genomic DNAs from 9 cases of Korean idiopathic azoospermia and 6 of Korean non-mosaic type of Klinefelter syndrome were used for the detection of Y chromosome microdeletions by polymerase chain reaction using 60 primers. Microdeletions of the Y chromosome were found in 1 of 9 (11.1%) patients with idiopathic azoospermia, whereas none was deleted in non-mosaic type of Klinefelter syndrome. This result suggests that Y chromosome microdeletions could be one of the etiologic factors in idiopathic azoospermia.
Exp Mol Med 2000 Dec 31
PMID:Y chromosome microdeletions in idiopathic azoospermia and non-mosaic type of Klinefelter syndrome. 1119 Feb 76

Targeted gene disruption has produced knockout mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1). These SF-1 knockout mice lacked adrenal glands and gonads, resulting in adrenocortical insufficiency and sex reversal of their internal and external genitalia. They also had impaired expression of pituitary gonadotropins and agenesis of the ventromedial hypothalamic nucleus (VMH), confirming roles of SF-1 at multiple levels of the hypothalamic-pituitary-steroidogenic tissue axis. Using the Cre-loxP system, we now have generated mice in which SF-1 is inactivated selectively in the anterior pituitary. These pituitary-specific SF-1 knockout mice were sterile and failed to exhibit sexual maturation. Histologically, their gonads were markedly hypoplastic, weighing only approximately 5% of the gonads of wild-type mice. Consistent with an important role of SF-1 in gonadotropes, there were no cells in the pituitary gland that expressed either follicle-stimulating hormone (FSH) or luteinizing hormone (LH). These pituitary-specific SF-1 knockout mice are a novel genetic model of hypogonadotropic hypogonadism and establish essential roles of SF-1 in gonadotropin expression.
Mol Cell Endocrinol 2001 Jun 20
PMID:Approaches to define the role of SF-1 at different levels of the hypothalamic-pituitary-steroidogenic organ axis. 1142 Jan 28

Gonadotropin Releasing Hormone (GnRH) is a key regulator of reproduction and sexual behaviour. During the last decade, embryological studies have clarified the question of the early development of GnRH-synthesising neurones before the onset of neurosecretion. These studies have revealed the existence of a topographical link between GnRH-synthesising neurones and the embryonic olfactory system, thereby shedding new light on Kallmann syndrome, a developmental disease characterised by the association of hypogonadotropic hypogonadism and anosmia (or hyposmia). Although Kallmann syndrome was identified as an inherited disease in the forties, familial cases of the disease are infrequent. However, the identification, by positional cloning strategies, of the gene underlying the X-chromosome linked form of the disease (KAL-1) has opened the way to molecular pathophysiology. KAL-1 encodes an extracellular glycoprotein of compound modular structure. The protein, named anosmin-1, has been produced in a transfected mammalian cell line and purified. Polyclonal and monoclonal antibodies have been generated, which allowed us to study the distribution of the protein during the period of human organogenesis (4--10 embryonic weeks), by immunohistofluorescence. During this developmental period, anosmin-1 is a locally restricted component of various extracellular matrices (interstitial matrices and basement membranes). Later in embryonic life, KAL-1 expression apparently becomes restricted to definite neuronal populations. Based on the distribution of anosmin-1 in the early olfactory system, the pathogenesis of the olfactory loss and GnRH deficiency in X-linked Kallmann syndrome is discussed.
Mol Cell Endocrinol 2001 Jun 20
PMID:Kallmann syndrome: towards molecular pathogenesis. 1142 Jan 33

Gonadotropin and GnRH receptors belong to the family of G protein coupled receptors. Gain of function mutations have been described, yielding constitutively active receptors. In the case of the LH receptor these dominant mutations determine familial male limited precocious puberty. Somatic mutations of this receptor may in some cases provoke Leydig-cell adenomas. The constitutive LH receptor is not associated with female precocious puberty. Inactivating mutations are recessive. Alterations in the GnRH receptor determine hypogonadotropic hypogonadism. The clinical diagnosis of this etiology of hypogonadism is extremely difficult, especially in sporadic cases. Mutations of gonadotropin receptors determine primary amenorrhea in girls, whereas in boys they are responsible for Leydig cell aplasia or hypoplasia (LH receptor) or of a variable alteration of spermatogenesis (FSH receptor). Mutations provoking only partial alterations of receptor functions are relatively more frequent, than those inducing complete receptor inactivity. They provide interesting insights into the physiology of GnRH and gonadotropin action.
Mol Cell Endocrinol 2001 Jun 20
PMID:Inherited disorders of GnRH and gonadotropin receptors. 1142 Jan 33

The clinical application of quantitative fluorescent polymerase chain reaction (QF-PCR) for rapid prenatal detection of chromosome aneuploidies has been limited in most studies to the detection of autosomal trisomies. Recently it has been shown that a newly identified highly polymorphic marker, termed X22, which maps to the Xq/Yq pseudoautosomal region of the sex chromosomes, used together with the X-linked short tandem repeat (STR) HPRT, allows the accurate detection of gonosome aneuploidies. We have developed a rapid assay, which includes these STR markers together with a sequence of the amelogenin region of the sex chromosomes and selected highly polymorphic autosomal STR. Two more X chromosome markers, as yet not used in previous QF-PCR applications, were also included in the assay. The molecular test was then used in a clinical trial on 551 uncultured amniotic fluid samples, allowing the assessment of copy number for chromosomes X, Y and 21 in 100% of cases. In the course of this study, two fetuses with Turner's syndrome and one with Klinefelter's syndrome were identified along with 17 autosomal trisomies. The assay proved to be so efficient and reliable that in most aneuploidy cases, in which ultrasound findings were in agreement with the molecular result, therapeutical interventions were possible without waiting for the result of cytogenetic analysis.
Mol Hum Reprod 2001 Oct
PMID:Clinical application of multiplex quantitative fluorescent polymerase chain reaction (QF-PCR) for the rapid prenatal detection of common chromosome aneuploidies. 1157 70

The aim of the study was to determine the rate of chromosome abnormalities in testicular sperm after intracytoplasmic sperm injection due to severe male factor infertility. The study groups included patient with non-obstructive azoospermia (n=9), obstructive azoospermia (n=10), Klinefelter's syndrome (n=5) and normal controls (n=6, groups I-VI, respectively). The mean serum levels of FSH 17.5+/-8.2 (P<0.05), 3.5+/-2.6, 29.8+/-13.0 (P<0.05) and 3.1+/-0.4 mIU/ml, respectively. The rates of chromosome abnormalities were 19.6% (P<0.001), 8.2% (P<0.001), 6.3 and 1.6%, respectively. Chromosomes X and Y were significantly more involved in the aneuploidy than chromosome 18 in groups I and II. The present findings demonstrate a linkage between gonadal failure (high serum FSH levels) and sperm chromosome abnormalities. Our findings may explain the increased incidence of perinatal sex chromosome abnormalities found in severe male factor patients. Patients with non-mosaic Klinefelter's syndrome have comparable risk for sex chromosomes aneuploidy as the rest of the patients with azoospermia. Therefore, genetic screening during pregnancy or before embryo replacement should be carefully considered in severe male factor patient following in vitro fertilization (IVF).
Mol Cell Endocrinol 2001 Oct 22
PMID:Studies on sperm chromosomes in patients with severe male factor infertility undergoing assisted reproductive technology treatment. 1157 28

Knockout mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1) revealed its essential roles at multiple levels of endocrine development and function. These SF-1 knockout mice lacked adrenal glands and gonads, thereby manifesting adrenal insufficiency and sex reversal of their internal and external genitalia. Their pituitary gonadotropes failed to express several markers of normal differentiated function, and they lacked a specific hypothalamic nucleus, the ventromedial hypothalamic nucleus (VMH). Using the Cre-loxP system, we generated mice whose gene encoding SF-1 was inactivated specifically in the anterior pituitary. These pituitary-specific SF-1 knockout mice were sterile and never matured sexually. Their gonads weighed only approximately 5% of the weight of wild-type gonads. SF-1 immunoreactivity was absent in the anterior pituitary but was unaffected in the adrenal cortex, validating the selectivity of the gene targeting strategy. Consistent with an important role of SF-1 in gonadotropes, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were markedly decreased in the pituitary-specific SF-1 knockout mice. The pituitary-specific SF-1 knockout mice are a novel genetic model of hypogonadotropic hypogonadism and establish essential roles of SF-1 in gonadotropin expression.
Mol Cell Endocrinol 2001 Dec 20
PMID:Pituitary-specific knockout of steroidogenic factor 1. 1173 91

SF-1 (steroidogenic factor-1) (NR5A1) and DAX-1 (dosage-sensitive sex-reversal, adrenal hypoplasia congenital, X chromosome) (NR0B1) are orphan nuclear receptors that are expressed in the adrenal gland, gonads, ventromedial hypothalamus (VMH), and pituitary gonadotrope cells. The function of these genes has been clarified by examining the consequences of naturally occurring mutations in humans, as well as targeted disruption of the genes in mice. Mutations in DAX1 cause adrenal hypoplasia congenita (AHC), an X-linked disorder characterized by adrenal insufficiency and failure to undergo puberty because of hypogonadotropic hypogonadism. Most DAX1 mutations introduce frameshifts and/or cause premature termination of the protein. Relatively few missense mutations have been described and all are located within the carboxy-terminal half of the protein. Transfection assays demonstrate that AHC-associated DAX1 mutations abrogate its ability to act as a transcriptional repressor of SF-1. Most boys affected with AHC present with adrenal insufficiency in early infancy, although a significant fraction present in later childhood or even as young adults. The degree of gonadotropin deficiency is also variable. With the exception of one mild missense DAX1 mutation, genotype-phenotype correlations have been elusive, suggesting an important role for modifier genes. Targeted mutagenesis of Dax1 (Ahch) in mice reveals an additional role in testis development and spermatogenesis. Similar abnormalities appear to be present in humans. Targeted mutagenesis of Sf1 (FtzF1) prevents gonadal and adrenal development, and causes male-to-female sex-reversal. A human XY individual with a heterozygous SF1 mutation presented with adrenal insufficiency and complete sex-reversal; this DNA-binding domain mutation prevents SF-1 stimulation of its target genes. In addition to their clinical relevance, studies of SF1 and DAX1 are proving useful for unraveling the genetic pathways that govern adrenal and gonadal development.
Mol Cell Endocrinol 2001 Dec 20
PMID:Phenotypic spectrum of mutations in DAX-1 and SF-1. 1173 90


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