Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of prokineticins (PKs), a novel family of bioactive peptides with a mitogenic action to endothelial cells of the endocrine gland and testis, on astrocytic functions were examined. Mouse cultured astrocytes expressed PK-R1 type PK receptors, while there was little expression of the PK-R2 type. PKs caused increases in astrocytic cytosolic Ca2+ levels and BrdU incorporation. Increases in Ca2+ levels by PK-2 were diminished by U73122 (a phospholipase C inhibitor). PK-induced BrdU incorporation was inhibited by U73122, GF109203 (a protein kinase C inhibitor) and PD98059 (a MEK/ERK inhibitor). These results indicate that PK receptors are expressed in astrocytes and regulate astrocytic proliferation.
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PMID:Expression of prokineticin receptors in mouse cultured astrocytes and involvement in cell proliferation. 1690 73

Kallmann syndrome (KS), the association of hypogonadotropic hypogonadism and anosmia, was described by Maestre de San Juan in 1856 and characterized as a hereditary condition by Franz Josef Kallmann in 1944. Many aspects such as pathogeny, phenotype and genotype in KS were described in the last fifteen years. The knowledge of this condition has grown fast, making it difficult to update. Here we review historical aspects of this condition and its discoverers and describe new findings regarding the embryogenesis of the olfactory bulb and GnRH secreting neuronal tracts that are important for understanding the association of hypogonadism and anosmia. Additionally, we describe the phenotypic and genotypic heterogeneity of KS, including five related genes (KAL-1, FGFR1, PROKR2, PROK2 e NELF), and discuss the function of each codified protein in migration and maturation of the olfactory and GnRH neurons, with data from in vitro and in vivo studies. Finally we describe the clinical phenotype of patients carrying these mutations.
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PMID:[Kallmann syndrome: a historical [corrected] clinical and molecular review]. 1834 92

This report documents a case with primary amenorrhea associated with sensorineural hearing loss and anosmia. The patient presented at 18 years of age with minimal sexual development and no prior menses. Her mother also presented late onset menarche, hearing loss and anosmia, and her father was also affected with hearing loss. A chromosome analysis of the patient showed 46, XX. Basal FSH and LH levels were in normal range, but the serum estradiol level was low. A serum estradiol elevation and follicular development were recognized after the injection of human menopausal gonadotropin. Genomic DNA sequencing of FSHB, FSHR, KAL1, FGFR1, PROK2 and PROKR2 did not show any mutation. Audiometry showed severe bilateral sensorineural hearing loss and smell testing confirmed a severely impaired olfactory function. These findings probably suggested a case of delayed puberty associated with sensorineural hearing loss and anosmia.
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PMID:Primary amenorrhea in an 18-year-old Japanese female with sensorineural hearing loss and anosmia: a new sydrome? 1848 May 58

The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease. Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance. Finally, mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic/oligogenic KS transmission modes. Notably, mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered.
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PMID:Kallmann syndrome. 1898 70

Kallmann syndrome (KS) combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism is due to gonadotropin-releasing hormone (GnRH) deficiency, which presumably results from a failure of the embryonic migration of neuroendocrine GnRH cells from the olfactory epithelium to the forebrain. This failure could be a consequence of the early degeneration of olfactory nerve and terminal nerve fibres, because the latter normally act as guiding cues for the migration of GnRH cells. Defects in GnRH cell fate specification, differentiation, axon elongation or axon targeting to the hypothalamus median eminence may, however, also contribute to GnRH deficiency, at least in some genetic forms of the disease. To date, five KS genes have been identified, namely, FGFR1, FGF8, PROKR2, PROK2, and KAL1. Mutations in these genes, however, account for barely 30% of all KS cases. Mutations in FGFR1, encoding fibroblast growth factor receptor 1, underlie an autosomal dominant form of the disease. Mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous or compound heterozygous states. These two genes are likely to be involved both in monogenic recessive and digenic or oligogenic KS transmission modes. Finally, KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked form of the disease. It is believed that anosmin-1 acts as an enhancer of FGF signalling and perhaps of prokineticin signalling too.
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PMID:The complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et al. 1898 92

Kallmann syndrome (KS) is the combination of hypogonadotropic hypogonadism and anosmia or hyposmia, two features that are also frequently present in CHARGE syndrome. CHARGE syndrome is caused by mutations in the CHD7 gene. We performed analysis of CHD7 in 36 patients with KS and 20 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH) in whom mutations in KAL1, FGFR1, PROK2 and PROKR2 genes were excluded. Three of 56 KS/nIHH patients had de novo mutations in CHD7. In retrospect, these three CHD7-positive patients showed additional features that are seen in CHARGE syndrome. CHD7 mutations can be present in KS patients who have additional features that are part of the CHARGE syndrome phenotype. We did not find mutations in patients with isolated KS. These findings imply that patients diagnosed with hypogonadotropic hypogonadism and anosmia should be screened for clinical features consistent with CHARGE syndrome. If such features are present, particularly deafness, dysmorphic ears and/or hypoplasia or aplasia of the semicircular canals, CHD7 sequencing is recommended.
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PMID:CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. 1902 38

Idiopathic Hypogonadotropic Hypogonadism (IHH), a syndrome of GnRH deficiency, is characterized by varying degrees of sexual development disruption. When associated with anosmia, it is termed Kallmann Syndrome (KS). Although it was identified as a hereditary disorder over half a century ago, only during the last two decades have specific putative IHH genes been revealed, including: KAL1, GnRHR, FGFR1, GPR54, PROK2, PROKR2, FGF8, CHD7, TAC3 and TAC3R. Human mutations have shed light on the molecular control of GnRH neuronal embryogenesis and have elucidated elements critical in sexual development. Furthermore, the newly proposed oligogenic model has challenged the dogma of IHH being a single gene disorder and has heightened appreciation for the functional overlap of distinct signaling systems. This review offers an historical perspective to gene discoveries in IHH, genotype-phenotype correlations, and finally, discussion of the evolving complexity of the new IHH genetic model, no longer simply characterized by Mendelian inheritance.
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PMID:The genetics of idiopathic hypogonadotropic hypogonadism:unraveling the biology of human sexual development. 1939 25

Idiopathic hypogonadotropic hypogonadism (IHH) has an incidence of 1-10 cases per 100,000 births. About 60% of patients with IHH present with associated anosmia, also known as Kallmann syndrome, characterized by total or partial loss of olfaction. Many of the gene mutations associated with Kallmann syndrome have been mapped to KAL1 or FGFR1. However, together, these mutations account for only about 15% of Kallmann syndrome cases. More recently, mutations in PROK2 and PROKR2 have been linked to the syndrome and may account for an additional 5-10% of cases. The remaining 40% of patients with IHH have a normal sense of smell. Prior to 2003, the only gene linked to normosmic IHH was the gonadotropin-releasing hormone receptor gene. However, mutations in this receptor are believed to account for only 10% of cases. Subsequently, mutations in KISS1R, TAC3 and TACR3 were identified as causes of normosmic IHH. Certain genes, including PROK2 and FGFR1, are associated with both anosmic and normosmic IHH. Despite recent advances in the field, the genetic causes of the majority of cases of IHH remain unknown. This Review discusses genes associated with hypogonadotropic disorders and the molecular mechanisms by which mutations in these genes may result in IHH.
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PMID:The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. 1970 80

The complex organization and regulation of the human hypothalamic-pituitary-gonadal axis render it susceptible to dysfunction in the face of a variety of genetic insults, leading to different degrees of hypogonadotrophic hypogonadism (HH). Although the genetic basis of some HH was recognized more than 60 years ago the first specific pathogenic defect, in the KAL1 gene, was only identified within the last 20 years. In the past decade, the rate of genetic discovery has dramatically accelerated, with defects in more than 10 genes now associated with HH. Several themes have emerged as the genetic basis of HH has gradually been uncovered, including the association of some genes such as FGFR1, FGF8, PROK2 and PROKR2, both with HH in association with hyposmia/anosmia (Kallmann syndrome) and with normosmic HH, thus blurring the clinical distinction between ontogenic and purely functional defects in the axis. Many examples of digenic inheritance of HH have also been reported, sometimes producing variable reproductive and accessory phenotypes within a family with non-Mendelian inheritance patterns. In strictly normosmic HH, human genetics has made a particularly dramatic impact in the past 6 years through homozygosity mapping in consanguineous families, first through identification of a key role for kisspeptin in triggering GnRH release, and very recently through demonstration of a critical role for neurokinin B in normal sexual maturation. This review summarises current understanding of the genetic architecture of HH, as well as its diagnostic and mechanistic implications.
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PMID:The recent genetics of hypogonadotrophic hypogonadism - novel insights and new questions. 1971 64

Human puberty is triggered by the reemergence of GnRH pulsatile secretion, with progressive activation of gonadal function. Several mutations have been identified in an increasing number of genes that influence the onset of puberty. Mutations in GNRH1, KISS1R and GNRHR genes cause normosmic IHH, interfering with the normal synthesis, secretion or action of GnRH. More recently, mutations in TAC3 and TACR3 genes, which encode neurokinin B and its receptor, have been implicated in normosmic IHH, although their precise functions in reproduction remain unclear. Mutations in KAL1, FGFR1, FGF8, PROK2 and PROKR2 are related to disruption of the development and migration of GnRH neurons, thereby resulting in Kallmann syndrome, a complex genetic condition characterized by isolated hypogonadotropic hypogonadism (IHH) and olfactory abnormalities. Furthermore, mutations in CHD7 gene, a major gene involved in the etiology of CHARGE syndrome, were also described in some patients with Kallmann syndrome and normosmic IHH. Notably, the evidence of association of some of the genes implicated with GnRH neurons development and migration with both Kallmann syndrome and normosmic IHH, blurring the simplest clinical distinction between ontogenic and purely functional defects in the axis. Digenic or oligogenic inheritance of IHH has also been described, illustrating the extraordinary genetic heterogeneity of IHH. Interestingly, rare gain-of-function mutations of the genes encoding the kisspeptin and its receptor were recently associated with central precocious puberty phenotype, indicating that the premature activation of the reproductive axis may be also caused by genetic mutations. These discoveries have yielded significant insights into the current knowledge of this important life transition.
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PMID:Genetics basis for GnRH-dependent pubertal disorders in humans. 2018 92


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