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)

Juvenile hemochromatosis (JH) is a characteristic form of genetic hemochromatosis with an early onset and severe clinical course leading to death if iron depletion treatment is not timely applied. Clinical complications include liver cirrhosis, heart failure, hypogonadotropic hypogonadism, and diabetes. In the present study we report the first case of JH described in Spain. Biochemical and genetic characteristics of the patient and relatives (parents and siblings) were investigated. No individual presented either the mutation at position 845 of the HFE gene or at position 750 of the TFR2 gene, associated with other types of hemochromatosis. Nevertheless, some individuals were homozygous for the mutation at position 187 of HFE. The hypothetic region of association with JH, located at chromosome 1q, was also investigated and results show that the patient presented a unique genotypic combination in 1q. The only brother with heavy iron deposits in hepatocytes was found to be heterozygous for the JH-associated region and homozygous for the HFE187 gene, suggesting a synergistic effect between both hemochromatosis-associated genes.
Blood Cells Mol Dis
PMID:Juvenile hemochromatosis in a Spanish family. 1248 7

Mutations in the DAX-1 (NR0B1) gene cause the X-linked form of adrenal hypoplasia congenita (AHC), which is constantly found associated with hypogonadotropic hypogonadism (HHG). DAX-1 encodes an atypical orphan member of the nuclear hormone receptor superfamily. DAX-1 acts at multiple levels to repress the expression of genes involved in steroid hormone metabolism through a potent transcriptional repression domain present in its C-terminus, which is similar to the nuclear receptors' ligand binding domain. All DAX-1 mutations causing AHC/HHG alter the protein C-terminal domain, impairing its nuclear localization and, consequently, its transcriptional repression activity. Here we show that DAX-1 AHC mutants have a misfolded conformation, which correlates with their cytoplasmic retention. Extensive structure-function analysis reveals that the chemical nature of amino acid residues at positions interested by AHC mutations and critical determinants in helix 12 affect DAX-1 nuclear localization and transcriptional silencing. Surprisingly, mutations in a conserved putative corepressor binding surface have a negative effect upon DAX-1 transcriptional repression only when they also affect protein expression levels. These data suggest that a folding defect underlies the impaired function of DAX-1 missense mutants found in AHC/HHG patients and that interactions with transcriptional cofactors different from known corepressors mediate DAX-1 silencing properties.
Hum Mol Genet 2003 May 01
PMID:Structure-function analysis reveals the molecular determinants of the impaired biological function of DAX-1 mutants in AHC patients. 1270 Jan 75

The unusual orphan member of the nuclear hormone receptor superfamily DAX-1 (NR0B1) owes its name to its double role in human pathology. On one side, duplications in Xp21, containing the DAX-1 gene, cause phenotypic sex reversal in XY individuals. On the other side, DAX-1 gene mutations are responsible for adrenal hypoplasia congenita, invariably associated with hypogonadotropic hypogonadism. DAX-1 functions as a global negative regulator of steroid hormone production by repressing the expression of multiple genes involved in the steroidogenic pathway. Here we review the mechanism of DAX-1 function in adrenal and gonadal differentiation, with special emphasis on recent results showing the critical role of DAX-1 protein misfolding in the pathogenesis of adrenal hypoplasia congenita.
Mol Endocrinol 2003 Aug
PMID:DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation. 1277 66

In the present study, we performed functional analyses of four mutations in the human GnRH receptor (GnRHR) gene, identified in patients with idiopathic hypogonadotropic hypogonadism. These mutations result in amino acid substitutions in the extracellular N-terminal domain (Thr32Ile), second extracellular loop (Cys200Tyr), third intracellular loop (Leu266Arg) and sixth transmembrane helix (Cys279Tyr). Immunocytochemical analysis of cells transfected with HA-tagged GnRHR constructs revealed that all four mutant receptors were present on the cell surface. However, all four mutant receptors failed to exhibit measurable specific GnRH binding and, except for Thr32Ile, any significant inositol phosphate accumulation after GnRH stimulation. In addition, Leu266Arg and Cys279Tyr receptors were unable to stimulate gonadotropin subunit or GnRHR gene promoter activity in response to GnRH. Interestingly, the Cys200Tyr mutant was able to stimulate gonadotropin subunit and GnRHR promoter activity, albeit with a higher EC(50) and a markedly reduced maximal response compared to wild type receptor. The Thr32Ile mutant was also able to stimulate gonadotropin subunit and GnRHR promoters, but with a further significant increase in EC(50). Similarly, this mutant partially retained the ability to activate extracellular signal-regulated kinase 1 and stimulate CRE-luciferase activity with an identical shift in EC(50). Taken together, the studies suggest that the Thr32Ile mutation reduces hGnRHR function primarily by reducing ligand binding affinity, and the Cys200Tyr mutation reduces cell surface receptor expression. All four amino acid substitutions interfered with ligand binding, and affected signal transduction and stimulation of gonadotropin and GnRHR gene expression in response to GnRH.
Mol Cell Endocrinol 2003 Jul 31
PMID:Four naturally occurring mutations in the human GnRH receptor affect ligand binding and receptor function. 1289 May 67

Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH in which the synthesis of all gonadal and adrenal cortical steroids is markedly impaired. Lipoid CAH may be caused by the defect in either the steroidogenic acute regulatory (StAR) protein or the P450scc. More than 34 different mutations in StAR gene have been identified. Clinically, most of the patients manifest adrenal insufficiency from 1 day to 2 months of age, but some patient show delayed onset of adrenal insufficiency. Affected 46, XY subjects do not show pubertal development, whereas affected 46, XX subjects undergo spontaneous feminization, breast development and cyclical vaginal bleeding at the usual age of puberty. X-linked adrenal hypoplasia congenital (AHC) is a rare congenital adrenal disorder characterized by severe adrenal insufficiency and hypogonadotropic hypogonadism. More than 80 different several intragenic mutations of DAX-1 have been identified. The failure of pubertal development may be caused by either abnormal hypothalamic or pituitary regulation of gonadotropin secretion. In addition, although the testicular steroidogenesis is largely intact, the functional maturity of Sertoli cells and also spermatogenesis are impaired. The type of mutation does not predict clinical phenotype. Thus, unified mechanism how DAX-1 gene defect gives rise to adrenal insufficiency, hypothalamic/pituitary hypogonadism and impaired spermatogenesis remains established.
J Steroid Biochem Mol Biol 2003 Jun
PMID:Molecular pathogenesis of lipoid adrenal hyperplasia and adrenal hypoplasia congenita. 1294 39

Targeted gene disruption has produced knockout (KO) mice globally deficient in the orphan nuclear receptor steroidogenic factor 1 (SF-1). These SF-1 KO mice lacked adrenal glands and gonads, and also had impaired expression of gonadotropins in pituitary gonadotropes and marked structural abnormalities of the ventromedial hypothalamic nucleus (VMH). To define the roles of SF-1 within discrete sites of the hypothalamic-pituitary-steroidogenic organ axis, we have sought to make tissue-specific SF-1 KO mice (as reviewed here). We first used adrenal transplants to restore adrenal function in global SF-1 KO mice, providing a physiological form of a "VMH-specific" KO to study the roles of SF-1 in weight regulation. These adrenal-transplanted SF-1 KO mice became obese due to decreased locomotor activity, providing a novel model of hypothalamic obesity. Mice with a pituitary-specific KO of SF-1 mediated by the Cre-loxP recombination strategy exhibited hypogonadotropic hypogonadism, revealing essential roles of SF-1 in pituitary function in vivo. Ongoing studies seek to inactivate SF-1 in the brain or specific gonadal cell types, thereby defining its roles in development and function at these sites. In addition, we review our use of bacterial artificial chromosome transgenesis to develop a fluorescent marker for cells that express SF-1.
Mol Cell Endocrinol 2004 Feb 27
PMID:Tissue-specific knockouts of steroidogenic factor 1. 1502 79

The GnRH receptor (GnRHR) is a heptahelical G protein-coupled receptor found in the plasma membrane of pituitary gonadotropes. GnRHR mutants isolated from patients with hypogonadotropic hypogonadism (HH) are frequently mislocalized proteins that can be restored to function by pharmacological chaperones. Nonfunctional HH mutants inhibit ligand binding and ligand-activated second messenger production by wild-type (WT) receptor when both are coexpressed in vitro. In this study, confocal microscopy of fluorescently labeled GnRHR was used to show that the dominant-negative effect, which occurs for human (but not for rodent) GnRHR, results from WT receptor retention in the endoplasmic reticulum by mislocalized mutants. Mutants hGnRHR(E90K), hGnRHR(L266R), and hGnRHR(S168R) were selected for study because they are known to be fully rescuable, partially rescuable, or nonrescuable (respectively) by a specific pharmacological chaperone. This chaperone corrects folding errors and promotes correct intracellular routing. Using this drug we showed that correcting routing of the mutant protein also rescues the WT receptor. Because of the large number of human diseases that appear to be caused by defective protein folding and subsequent mislocalization, it is likely that endoplasmic reticulum retention is a common cause of dominant-negative actions for other diseases involving G protein-coupled receptors, as appears to be the case in HH and for which there exists a potential therapeutic agent.
Mol Endocrinol 2004 Jul
PMID:Human loss-of-function gonadotropin-releasing hormone receptor mutants retain wild-type receptors in the endoplasmic reticulum: molecular basis of the dominant-negative effect. 1510 40

Although testicular development has been shown to be variably impaired in XY patients with distal 9p monosomy, ovarian and other genitourinary phenotype has poorly been studied in XX patients monosomic for the distal 9p region. Thus, we studied a 13-month-old infant with 46,XX,der(9)t(9;10)(p23;p13) (case 1) and an 11-year-old girl with 46,XX,der(9)t(9;16)(p23;q22) (case 2). Case 1 had primary hypogonadism (basal serum follicle stimulating hormone [FSH], 40.0 mIU/mL; leteinizing hormone [LH], 1.2 mIU/mL; estradiol [E2], <10 pg/mL), whereas case 2 had age-appropriate pubertal development (breast, Tanner stage 4; pubic hair, Tanner stage 3; menarche 11.7 years of age) and hormone values (FSH, 7.3 mIU/mL; LH, 6.7 mIU/mL; E2, 47 pg/mL). In addition, case 1 had hypoplastic labia majora, short distance between the vaginal orifice and the anus, and five renal cysts, and case 2 had anal atresia, short distance between the vaginal orifice and the anus, bilateral hydronephrosis of grade 3 with probable ureteropelvic junction stenosis, and renal dysfunction (serum creatinine, 1.52 mg/dL; urea nitrogen, 34.5mg/dL). Fluorescence in situ hybridization analysis for five regions and microsatellite analysis for 10 loci on 9p confirmed hemizygosity for the distal 9p region with the breakpoints between IFNA and D9S285 in case 1 and between D9S168 and D9S286 in case 2. The results, in conjunction with the previous data in XX patients with molecularly defined distal 9p monosomy, are consistent with the presence of a gene(s) involved in the development of indifferent gonad or subsequent ovarian differentiation in a approximately 11 Mb region distal to D9S168. In addition, it is possible that a gene(s) for anoperineal and renal development also maps distal to D9S168 and that for external genital development maps distal to D9S285 at the position approximately 16 Mb from the 9p telomere.
Mol Genet Metab 2004 Jun
PMID:Genitourinary phenotype in XX patients with distal 9p monosomy. 1517 6

Kallmann syndrome (KAL) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. KAL is phenotypically and genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991. KAL1 encodes anosmin-1, an approximately 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann syndrome (KAL2), combined with the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of anosmin-1 is to enhance FGF signaling and suggest that the gender difference in anosmin-1 dose (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.
J Mol Med (Berl) 2004 Nov
PMID:Kallmann syndrome: fibroblast growth factor signaling insufficiency? 1536 36

DAX1 (dosage sensitive sex reversal (DSS), adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1) encoded by the gene NR0B1, is an unusual orphan nuclear receptor that when mutated causes AHC with associated hypogonadotropic hypogonadism (HH), and when duplicated causes DSS. DAX1 expression has been shown in all regions of the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis during development and in adult tissues, suggesting a critical role for DAX1 in the normal development and function of this axis. Steroidogenic factor 1 (SF1, NR5A1) knockout mice show similar developmental defects as AHC and HH patients, but paradoxically, DAX1 is a negative coregulator of SF1 transactivation. The function of DAX1 as an antagonist of SF1 in gonadal development is consistent with the fact that in humans, duplication of the region of the X chromosome containing DAX1 causes a similar phenotype as mutations in SF1. However, how disruption of DAX1 leads to adrenal, hypothalamic, and pituitary developmental defects similar to SF1 disruption remains to be clarified. The exact mechanism of DAX1 action in each of these tissues during adulthood and critical stages of development are not fully understood. Recent evidence suggests a broader functional role for DAX1 as a negative coregulator of estrogen receptor (ER, NR3A1-2), liver receptor homologue-1 (LRH-1, NR5A2), androgen receptor (AR, NR3C4), and progesterone receptor (PR, NR3C3), each by distinct repression mechanisms. DAX1 may have pleiotropic roles in addition to its function as a negative regulator of steroidogenesis during the development and adult function of the HPAG axis.
Mol Genet Metab
PMID:Molecular mechanisms of DAX1 action. 1546 21


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