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

We looked for a possible association between Klinefelter syndrome (KFS) and microdeletions in the Y chromosome in Turkish KFS patients. We examined the frequency of KFS in male patients with proven non-obstructive azoospermia and the types of Y chromosome microdeletions in these KFS patients. Fifty azoospermic patients and 50 fertile men were included in this study. KFS was found in 14 azoospermic patients. Y chromosome microdeletions were found in eight KFS patients. Azoospermia factor locus c (AZFc) was the most commonly deleted interval in KFS patients. All KFS patients had elevated plasma follicle-stimulating hormone and luteinizing hormone concentrations, but they had normal plasma testosterone concentrations. Testis biopsy of five samples with Y microdeletions revealed Sertoli cell-only syndrome. No Y microdeletions were found in the fertile group. We concluded that there could be an association between the AZFc region and KFS. Screening for this should be part of diagnostic work-up, particularly in those considering assisted reproduction.
Genet Mol Res 2010 Jun 29
PMID:The azoospermia factor locus-c region was found to be related to Klinefelter syndrome in Turkish patients. 2060 8

Klinefelter syndrome is the most common chromosome abnormality in humans. The estimated prevalence is one in 500 to one in 1000 males but due to the widely variable and often aspecific features, only one in four cases are recognized. The most specific clinical features which can be observed at adult age are small testes, gynecomastia, female distribution of fat and body hair, slightly increased body length due to an increased leg length and azoospermia. Cognition is characterized by verbal deficits and psychosocial features include autistiform behavior. Structural brain abnormalities have been observed by MRI, such as decreased brain volumes and a decrease of asymmetry in areas corresponding to language performance. In the vast majority of cases a non-mosaic 47,XXY karyotype is observed. Parental imprinting of the extra X chromosome, variable inactivation of some X-chromosomal genes and CAG repeat length polymorphism of the androgen receptor may all be related to the variability of the phenotype. Surgical procedures of obtaining sperm in combination with repeated intracytoplasmic sperm injection/in vitro fertilization treatment may allow up to one in four men with Klinefelter syndrome to father children.
Expert Rev Mol Diagn 2010 Sep
PMID:Klinefelter syndrome: clinical and molecular aspects. 2084

Holoprosencephaly (HPE), the most common malformation of the human forebrain, may arise due to interacting genetic and environmental factors. To date, at least 12 contributory genes have been identified. Fibroblast growth factor 8 (Fgf8) belongs to the FGF family of genes expressed in several developmental signaling centers, including the anterior neural ridge, which is implicated in midline anomalies in mice. In humans, FGF8 mutations have been previously reported in facial clefting and in hypogonadotropic hypogonadism, but have not been reported in patients with HPE. We screened 360 probands with HPE for sequence variations in FGF8 using High Resolution DNA Melting (HRM) and sequenced all identified variations. Here we describe a total of 8 sequence variations in HPE patients, including a putative loss-of-function mutation in 3 members of a family with variable forms of classic HPE, and relate these findings to the phenotypes seen in other conditions.
Mol Syndromol 2010
PMID:A Hypomorphic Allele in the FGF8 Gene Contributes to Holoprosencephaly and Is Allelic to Gonadotropin-Releasing Hormone Deficiency in Humans. 2104 58

Kallmann syndrome (KS) is a genetic disease characterized by hypogonadotropic hypogonadism and impaired sense of smell. The genetic causes underlying this syndrome are still largely unknown, but are thought to be due to a developmental defect in the migration of gonadotropin-releasing hormone (GnRH) neurons. Understanding the causes of the disease is hampered by lack of appropriate mouse models. GnRH neurons are hypothalamic cells that centrally control reproduction in mammals by secreting the GnRH decapeptide into the portal blood vessels of the pituitary to stimulate the production of gonadotropins. During development, these cells are born in the nasal placode outside the brain and migrate in association with olfactory/vomeronasal axons to reach the forebrain and position themselves in the hypothalamus. By combining the analysis of genetically altered mice with in vitro models, we demonstrate here that a secreted guidance cue of the class 3 semaphorin family, SEMA3A, is essential for the development of the GnRH neuron system: loss of SEMA3A signalling alters the targeting of vomeronasal nerves and the migration of GnRH neurons into the brain, resulting in reduced gonadal size. We found that SEMA3A signals redundantly through both its classical receptors neuropilin (NRP) 1 and, unconventionally, NRP2, while the usual NRP2 ligand SEMA3F is dispensable for this process. Strikingly, mice lacking SEMA3A or semaphorin signalling through both NRP1 and NRP2 recapitulate the anatomical features of a single case of KS analysed so far, and may therefore be used as genetic models to elucidate the pathogenesis of KS.
Hum Mol Genet 2011 Jan 15
PMID:Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism. 2105 4

The pathogenic mechanisms whereby the Thr104Ile and Tyr108Cys mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene cause hypogonadotropic hypogonadism in humans are unknown. Transient expression of Thr104Ile and Tyr108Cys mutants in COS-7 cells revealed that both GnRHR mutants neither bind nor respond to agonist. Removal of Lys191 rescued function of both mutants, while addition of a carboxyl-terminal targeting sequence only rescued function of the Thr104Ile mutant. Exposure to the pharmacoperone In3 rescued almost completely Thr104Ile mutant function to wild-type levels, whereas rescue was partial for the Tyr108Cys GnRHR. Additional mutations that block formation of bridges involving Cys108 showed that a Cys108-Cys200 disulfide bridge is the predominant moiety formed in the Tyr108Cys mutant. Thr104Ile and Tyr108Cys GnRHRs are misfolded structures whose function is rescuable by genetic and/or pharmacological strategies. The Tyr108Cys mutant forms an aberrant disulfide bridge that prevents formation of the required Cys14-Cys200 bridge essential for GnRHR plasma membrane expression.
Mol Cell Endocrinol 2011 Apr 30
PMID:Biochemical mechanism of pathogenesis of human gonadotropin-releasing hormone receptor mutants Thr104Ile and Tyr108Cys associated with familial hypogonadotropic hypogonadism. 2127 37

Congenital deficiency of the leptin receptor is a very rare cause of severe early-onset obesity. To date, only 9 families have been reported in the literature to have mutations in the leptin receptor gene. The clinical features include severe early onset obesity, severe hyperphagia, hypogonadotropic hypogonadism, and T cell and neuroendocrine/metabolic dysfunction. Here we report two cousins with severe early onset obesity and recurrent respiratory tract infections. Their serum leptin levels were elevated but they were within the range predicted by the elevated fat mass in both cousins. Direct sequencing of the entire coding sequence of the leptin receptor gene revealed a novel homozygous missense mutation in exon 6, P316T. The mutation was found in the homozygous form in both cousins and in the heterozygote state in their parents. This mutation was not found in 200 chromosomes from 100 unrelated normal weight control subjects of Egyptian origin using PCR-RFLP analysis. In conclusion, finding this new mutation in the LEPR beside our previous mutation in the LEP gene implies that monogenic obesity syndromes may be common in the Egyptian population owing to the high rates of consanguineous marriages. Further screening of more families for mutations in LEP, LEPR, and MC4 might confirm this assumption.
Mol Genet Metab 2011 Apr
PMID:Homozygosity for a novel missense mutation in the leptin receptor gene (P316T) in two Egyptian cousins with severe early onset obesity. 2130 29

GnRH is the central regulator of reproductive function responding to central nervous system cues to control gonadotropin synthesis and secretion. GnRH neurons originate in the olfactory placode and migrate to the forebrain, in which they are found in a scattered distribution. Congenital idiopathic hypogonadotropic hypogonadism (CIHH) has been associated with mutations or deletions in a number of genes that participate in the development of GnRH neurons and expression of GnRH. Despite the critical role of GnRH in mammalian reproduction, a comprehensive understanding of the developmental factors that are responsible for regulating the establishment of mature GnRH neurons and the expression of GnRH is lacking. orthodenticle homeobox 2 (OTX2), a homeodomain protein required for the formation of the forebrain, has been shown to be expressed in GnRH neurons, up-regulated during GnRH neuronal development, and responsible for increased GnRH promoter activity in GnRH neuronal cell lines. Interestingly, mutations in Otx2 have been associated with human hypogonadotropic hypogonadism, but the mechanism by which Otx2 mutations cause CIHH is unknown. Here we show that deletion of Otx2 in GnRH neurons results in a significant decrease in GnRH neurons in the hypothalamus, a delay in pubertal onset, abnormal estrous cyclicity, and infertility. Taken together, these data provide in vivo evidence that Otx2 is critical for GnRH expression and reproductive competence.
Mol Endocrinol 2011 May
PMID:Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism. 2143 60

CHARGE is a multiple congenital anomaly disorder and a common cause of pubertal defects, olfactory dysfunction, growth delays, deaf-blindness, balance disorders and congenital heart malformations. Mutations in CHD7, the gene encoding chromodomain helicase DNA binding protein 7, are present in 60-80% of individuals with the CHARGE syndrome. Mutations in CHD7 have also been reported in the Kallmann syndrome (olfactory dysfunction, delayed puberty and hypogonadotropic hypogonadism). CHD7 is a positive regulator of neural stem cell proliferation and olfactory sensory neuron formation in the olfactory epithelium, suggesting that the loss of CHD7 might also disrupt development of other neural populations. Here we report that female Chd7(Gt/+) mice have delays in vaginal opening and estrus onset, and erratic estrus cycles. Chd7(Gt/+) mice also have decreased circulating levels of luteinizing hormone and follicle-stimulating hormone but apparently normal responsiveness to gonadotropin-releasing hormone (GnRH) agonist and antagonist treatment. GnRH neurons in the adult Chd7(Gt/+) hypothalamus and embryonic nasal region are diminished, and there is decreased cellular proliferation in the embryonic olfactory placode. Expression levels of GnRH1 and Otx2 in the hypothalamus and GnRHR in the pituitary are significantly reduced in adult Chd7(Gt/+) mice. Additionally, Chd7 mutant embryos have CHD7 dosage-dependent reductions in expression levels of Fgfr1, Bmp4 and Otx2 in the olfactory placode. Together, these data suggest that CHD7 has critical roles in the development and maintenance of GnRH neurons for regulating puberty and reproduction.
Hum Mol Genet 2011 Aug 15
PMID:Reproductive dysfunction and decreased GnRH neurogenesis in a mouse model of CHARGE syndrome. 2159 39

GnRH and its receptor GnRHR are key regulators of the hypothalamo-pituitary axis. They modulate the secretion of LH and FSH gonadotropins and therefore, the development and maturation of gonads in fetal life as well as after birth. Congenital functional defect of this axis results in isolated hypogonadotropic hypogonadism (IHH). Several natural mutations causing IHH without anosmia have now been identified in GnRHR or GnRH genes. These mutations inactivate GnRHR or its ligand function and cause highly variable phenotypes, ranging from partial to complete gonadotropic deficiencies. The present review describes the published natural GnRHR mutations and tries to correlate them with the corresponding phenotypes according to the different steps of the GnRH system development.
Mol Cell Endocrinol 2011 Oct 22
PMID:GnRH receptor mutations in isolated gonadotropic deficiency. 2164 87

Mutations in FGFR1, GNRHR, PROK2, PROKR2, TAC3, or TACR3 underlie isolated hypogonadotropic hypogonadism (IHH) with clinically variable phenotypes, and, by causing incomplete intrauterine activation of the hypothalamic-pituitary-gonadal axis, may lead to cryptorchidism. To investigate the role of defects in these genes in the etiology of isolated cryptorchidism, we screened coding exons and exon-intron boundaries of these genes in 54 boys or men from 46 families with a history of cryptorchidism. Control subjects (200) included 120 males. None of the patients carried mutation(s) in FGFR1, PROK2, PROKR2, TAC3 or TACR3. Two of the 46 index subjects with unilateral cryptorchidism were heterozygous carriers of a single GNRHR mutation (Q106R or R262Q), also present in male controls with a similar frequency (3/120; p=0.62). No homozygous or compound heterozygous GNRHR mutations were found. In conclusion, cryptorchidism is not commonly caused by defects in genes involved in IHH.
Mol Cell Endocrinol 2011 Jul 20
PMID:Isolated cryptorchidism: no evidence for involvement of genes underlying isolated hypogonadotropic hypogonadism. 2166 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>