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)

When normal development and growth of the calvarial sutures is disrupted, craniosynostosis (premature calvarial suture fusion) may result. Classical craniosynostosis syndromes are autosomal dominant traits and include Apert, Pfeiffer, Crouzon, Jackson-Weiss, and Saethre-Chotzen syndromes. In these conditions, there is premature fusion of skull bones leading to an abnormal head shape, ocular hypertelorism with proptosis, and midface hypoplasia. It is known that mutations in the fibroblast growth factor receptors 1, 2, and 3 cause craniosynostosis. We report on a child with a clinically diagnosed Pfeiffer syndrome that shows the missense point mutation Q289P in exon 8 of the FGFR2 gene. This is a mutation not previously described in the Pfeiffer syndrome but reported in the Crouzon, Jackson-Weiss, and Saethre-Chotzen syndromes. In this paper, we propose the concept that these disorders may represent one genetic condition with phenotypic variability.
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PMID:Q289P mutation in the FGFR2 gene: first report in a patient with type 1 Pfeiffer syndrome. 1906 59

Nerve growth factor (NGF) is a well-known neurotrophic factor essential for the survival and maintenance of sensory and sympathetic neurons. Congenital insensitivity to pain with anhidrosis (CIPA) is a genetic disorder due to loss-of-function mutations in the NTRK1 (also known as TRKA) gene encoding TrkA, a receptor tyrosine kinase for NGF. Patients with CIPA provide us a rare opportunity to explore the developmental and physiological function of the NGF-dependent neurons in behavior, cognitive, and mental activities that are not available in animal studies. Here, I discuss the significance of findings that patients with CIPA lack NGF-dependent neurons, including interoceptive polymodal receptors, sympathetic postganglionic neurons, and probably several types of neurons in the brain. They also exhibit characteristic emotional behavior or problems. Together, the NGF-TrkA system is essential for the establishment of a neural network for interoception and homeostasis that may underlie 'gut feelings'. Thus, NGF-dependent neurons play a crucial role in emotional experiences and decision-making processes. Prospective studies focused on these neurons might provide further insights into the neural basis of human emotion and feeling.
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PMID:Nerve growth factor, interoception, and sympathetic neuron: lesson from congenital insensitivity to pain with anhidrosis. 1920 60

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

The pathogenesis of late normal tissue fibrosis after high-dose ionizing radiation involves multiple cell types and signalling pathways but is not well understood. To identify the molecular changes occurring after radiotherapy, paired normal tissue samples were collected from the non-irradiated breast and from the treated breast of women who had undergone curative radiotherapy for early breast cancer months or years previously. As radiation may induce distinct transcriptional changes in the different components of the breast, laser capture microdissection and gene expression microarray profiling were performed separately for epithelial and stromal components and selected genes were validated using immunohistochemistry. In the epithelial compartment, a reduction of KIT (c-Kit; CD117) and a reciprocal increase in ESR1 (oestrogen receptor-alpha, ERalpha) mRNA and protein levels were seen in irradiated compared to non-irradiated samples. In the stromal compartment, extracellular matrix genes including FN1 (fibronectin 1) and CTGF (connective tissue growth factor; CCN2) were increased. Further investigation revealed that c-Kit and ERalpha were expressed in distinct subpopulations of luminal epithelial cells. Interlobular c-Kit-positive mast cells were also increased in irradiated cases not showing features of post-radiation atrophy. Pathway analysis revealed 'cancer, reproductive system disease and tumour morphology' as the most significantly enriched network in the epithelial compartment, whereas in the stromal component, a significant enrichment for 'connective tissue disorders, dermatological diseases and conditions, genetic disorder' and 'cancer, tumour morphology, infection mechanism' networks was observed. These data identify previously unreported changes in the epithelial compartment and show altered expression of genes implicated in late normal tissue injury in the stromal compartment of normal breast tissue. The findings are relevant to both fibrosis and atrophy occurring after radiotherapy for early breast cancer.
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PMID:Genome-wide transcriptomic profiling of microdissected human breast tissue reveals differential expression of KIT (c-Kit, CD117) and oestrogen receptor-alpha (ERalpha) in response to therapeutic radiation. 1956 35

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable disorder of impaired behavioral inhibition, increased motor activity, and inattention. The norepinephrine transporter (NET, SLC6A2) represents an important candidate gene for contribution to ADHD because it regulates catecholamine extracellular and tissue concentrations and contributes to executive functions disrupted in ADHD, and NET is a target for most effective ADHD therapeutics. We identified four NET coding single nucleotide polymorphisms (SNPs) in two ADHD sample sets; two SNPs produce protein variants (T283M, V245I), one of which, T283M, is a novel variant. Examination of the maternal family members through whom the T283M mutation was transmitted, provided no additional ADHD diagnoses. Given the previous identification of a NET mutation that contributes to a familial tachycardia syndrome, we examined autonomic function to reveal in the proband the highest standing-induced increase in heart rate among the ADHD subjects examined. We measured [3H]NE and [3H]dopamine transport for T283M, V245I, and a previously identified NET variant, T283R. T283M and V245I demonstrated decreased substrate transport, as did T283R, suggesting that the T283 residue is sensitive to mutation. Identification of polymorphic sites within NET, specifically those that produce functional consequences, is one critical step in elucidating the genetic variation contributing to the heritable component of diseases such as ADHD.
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PMID:Novel and functional norepinephrine transporter protein variants identified in attention-deficit hyperactivity disorder. 1969 24

Aldosterone regulates blood pressure through its effects on the cardiovascular system and kidney. Aldosterone can also contribute to the development of hypertension that leads to chronic pathologies such as nephropathy and renal fibrosis. Aldosterone directly modulates renal cell proliferation and differentiation as part of normal kidney development. The stimulation of rapidly activated protein kinase cascades is one facet of how aldosterone regulates renal cell growth. These cascades may also contribute to myofibroblastic transformation and cell proliferation observed in pathological conditions of the kidney. Polycystic kidney disease is a genetic disorder that is accelerated by hypertension. EGFR-dependent proliferation of the renal epithelium is a factor in cyst development and trans-activation of EGFR is a key feature in initiating aldosterone-induced signalling cascades. Delineating the components of aldosterone-induced signalling cascades may identify novel therapeutic targets for proliferative diseases of the kidney.
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PMID:Aldosterone as a renal growth factor. 1978 95

Hereditary gastrointestinal stromal tumor (GIST) syndrome is a rare autosomal dominant genetic disorder originated by germline mutations in the KIT or PDGFRA genes. We report the third family with hereditary predisposition to GIST due to the KIT Exon 17 germline mutation p.Asp820Tyr and characterize the cytogenetic progression pathways followed by different GIST sharing the same primary genetic event, using a combination of chromosome banding, comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH) analyses. The missense mutation p.Asp820Tyr was detected in the proband's rectal and gastric GIST, as well as in his aunt's GIST epiplon metastasis. The mutation p.Asp820Tyr was subsequently also found in the proband's peripheral blood DNA, as well as in that of 4 of 10 relatives thus far analyzed. CGH analysis revealed loss of 14q and 15q in the proband's gastric lesion, whereas FISH analysis of the proband's rectal GIST did not detect loss of 14q and 15q, but instead loss of 4q and 22q and gain of 20q, indicating that the two tumors were independent GIST. Chromosome banding and CGH analyses of the aunt's GIST epiplon metastasis revealed multiple cytogenetic alterations, including 1p loss, but none in common with the two proband's GIST. We conclude that, although the patients share the same KIT Exon 17 germline mutation, the multiple GIST analyzed followed different pathogenetic progression pathways, each of which did not significantly differ from what has been described in sporadic GIST.
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PMID:Hereditary gastrointestinal stromal tumors sharing the KIT Exon 17 germline mutation p.Asp820Tyr develop through different cytogenetic progression pathways. 1984 91

Disrupted fibroblast growth factor receptor (FGFR)1 signalling has been shown to cause Kallmann syndrome (KS), a human genetic disorder characterised by olfactory bulb dysgenesis and hypogonadotrophic hypogonadism. Loss-of-function mutations in the KS gene KAL-2/FGFR1 account for roughly 10% of KS cases, leading to the autosomal dominant form of the disease. Anosmin-1, the KAL-1 gene product underlying X-linked KS, modulates FGFR1 signalling via regulation of FGF2/FGFR1/heparin signalling complex assembly and activity. This review covers recent advances in the potential interactions of KS-associated molecules within the FGFR1 signalling complex, and demonstrates a novel mechanism of pre-signalling modulation that mechanistically links an autosomal dominant and sex-linked mode of inheritance of this disease, highlighting the central role of FGFR1 signalling in KS.
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PMID:Novel insights in FGFR1 regulation: lessons from Kallmann syndrome. 2011 45

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

Kallmann syndrome (KS) is a heterogeneous genetic disorder that associates variable gonadotropin-releasing hormone (GnRH) deficiency with anosmia and, sometimes, other non-reproductive clinical features. X-linked recessive, as well as autosomal recessive and dominant modes of transmission have been described. The first KS-related gene to be described (KAL1) was in the X-linked form. The second gene (KAL2) was initially unexpected, as it was known to encode the fibroblast growth receptor 1 (FGFR1). Its consideration as a candidate gene arose as a result of cases with contiguous gene syndrome and, initially, mutations were mostly described in familial cases with autosomal dominant transmission of KS. Since its initial discovery, numerous mutations of FGFR1 have been described in several functional domains of the receptor. Genotype-phenotype correlations have shown that some clinical features associated with KS, such as loss of nasal cartilage, hearing impairment, and anomalies of the limbs seem to be mainly associated with KAL2 mutations. The role of FGFR1 in the normal development of the olfactory bulb explains the association of anosmia with GnRH deficiency in FGFR1-mutated patients. Phenotype analysis indicates that FGFR1 is involved in normal migration of GnRH fetal neurons, but this is clearly not the whole story as a substantial proportion of KAL2-mutated individuals have normosmic GnRH deficiency. Finally, recent additional observations, notably using animal models, but also the description of human mutations in a specific ligand of FGFR1, FGF8, are beginning to shed light on the pathogenesis of GnRH deficiency in general, not just KS.
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PMID:FGFR1 mutations in Kallmann syndrome. 2038 85


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