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PubMed2005

Renal tubular transport and the genetic basis of hypertensive disease.

Several monogenic hypertensive disorders are caused by genetic mutations leading to the deranged function and/or regulation of renal tubular NaCl transport, such as mutations of the renal epithelial Na+ channel (ENaC) in Liddle syndrome, of the kinase WNK1 (with no K) in Gordon syndrome, and of the mineralocorticoid receptor, or of 11beta-hydroxysteroid dehydrogenase. Moreover, excessive formation of aldosterone in glucocorticoid-remediable hypertension leads to severe hypertension. Conversely, impaired function of the Na+,K+,2Cl- cotransporter (NKCC2), the renal outer medullary K+ channel (ROMK1), and the renal epithelial Cl- channel ClCKb/Barttin causes Bartter syndrome and defective Na+,Cl+ cotransporter (NCCT) Gitelman syndrome, salt-wasting disorders with hypotension. These monogenic disorders are rare, but illustrate the significance of renal tubular transport in blood pressure regulation. There is little doubt, however, that deranged renal salt reabsorption significantly contributes to essential hypertension polymorphisms of several genes participating in the regulation of renal Na+ transport have been shown to be associated with blood pressure and prevalence of hypertension. Two common genes will be discussed in more detail. The first encodes the renal Cl- channel ClCKb. A gain-of-function mutation of ClCKb, increasing channel activity by 7- to 20-fold is found in approximately 20% of unselected Caucasians and 40% of an unselected African population. The second common gene variant (prevalence, 3%-5% in unselected Caucasians), to be discussed in more detail, affects the serum and glucocorticoid inducible kinase SGK1, a kinase upregulated by mineralocorticoids and enhancing the activity of ENaC, ROMK, and Na+/K+ATPase. Both gene variants are associated with slightly increased blood pressure. SGK1 further stimulates the glucose transporter SGLT1, and the SGK1 gene variant correlates, in addition, with increased body mass index.

Animals↗
PubMed2006

Biochemical and molecular characterization of the novel BRAF(V599Ins) mutation detected in a classic papillary thyroid carcinoma.

Activating mutations of the BRAF gene are the most common genetic alterations in papillary thyroid carcinomas (PTCs) and the T1799A transversion, resulting in BRAFV600E, appeared virtually unique in this cancer type. Here, we report on the identification in a classic PTC of a novel BRAF mutation, namely a 1795GTT insertion, resulting in BRAFV599Ins, and describe its biochemical and molecular characterization. Kinase assays carried out on BRAFV599Ins and BRAFV600E revealed a three- to five-fold increase in the enzymatic activity of both mutants with respect to BRAFWT. Similarly, evaluation of BRAF-induced phosphorylation of MEK, MAPK and RSK revealed a significant MAPK cascade activation in cells expressing BRAFV599Ins or BRAFV600E, but not in cells expressing BRAFWT. Molecular dynamic simulations showed a destabilization of the inactive conformation of the enzyme in both BRAFV599Ins and BRAFV600E mutants, but not in BRAFWT. The analysis of the interaction energies inside the catalytic site allowed to demonstrate the presence of repulsive electrostatic forces acting on the activation loop and moving from inward to outward of the mutant enzymes. Finally, focus assays in NIH-3T3 cells confirmed a high transformation rate in the cells transfected either with BRAFV599Ins or BRAFV600E. In conclusion, this study demonstrated that BRAFV599Ins, as BRAFV600E, is a 'gain of function' mutation, characterized by a constitutive catalytic activation, which accounts for its causative role in the studied PTC.

Aged↗
PubMed1999

Ocular manifestations in children and adolescents with thyrotoxicosis.

Thyrotoxicosis is a rare disorder in childhood and adolescence. The frequency ranges from 0.1 in 100000 in young children to 3.0 in 100000 in adolescents and the most frequent cause is Graves' disease. Few children and adolescents suffer from thyrotoxicosis during the course of autoimmune thyroiditis and non-autoimmune hyperthyroidism due to constitutively active mutations of the TSH-receptor have been reported in single patients with neonatal hyperthyroidism and rare familial cases. From a survey of the literature it is apparent that infiltrative ophthalmopathy is very rare in children and adolescents. Milder ocular manifestations as retraction of the upper eyelid, upper lid lag and "staring eyes" are reported in varying frequencies ranging from 25 to 60% of all patients. In our own series of 43 children and adolescents (34 females, 9 males) with thyrotoxicosis only 16 (37%) had clear ocular manifestations of upper lid retraction, lid lag and slight protrusio bulbi. However, only three of of them had soft tissue involvement and significant exophtalmus. In none of the patient corneal or optic nerve involvement or paralysis of the extraorbital muscles was observed. Newborns with congenital hyperthyroidism due to maternal Graves' disease seem to present significant transitory ocular manifestations more frequently, but again no infiltrative ophtalmopathy requiring specific therapy is present. Recently at least four different newborns with congenital thyrotoxicosis due to gain-of-function mutations of the TSH-receptor have been reported, who also had significant ocular manifestations. The presence of staring eyes, slight proptosis and lid retraction in these newborns without any autoimmune or inflammatory process supports the hypothesis that these ocular manifestations are caused by the increased thyroid hormone actions. The involvement of the eyes is usually transitory in newborns as well as in children and adolescents and the symptoms usually disappear when euthyroidism is restored. The administration of steroids therefore is restricted to the rare severe cases with eye muscle or soft tissue involvement. There are no reports on surgical decompression or orbital irradiation therapy of ophtalmopathy in children and adolescents, which again indicates that ocular involvement in thyrotoxicosis in children and adolescents is less frequent and much less severe than in adults.

Adolescent↗
PubMed2001

Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study.

The FLT3 gene is mutated by an internal tandem duplication (ITD) in 20-25% of adults with acute myeloid leukemia (AML). We studied 82 adults <60 years of age with primary AML and normal cytogenetics, who received uniform high-dose therapy and found FLT3 ITD in 23 (28%) patients. When the 23 FLT3 ITD+ cases were compared with the 59 cases with wild-type (WT) FLT3, disease-free survival (DFS) was inferior (P = 0.03), yet overall survival (OS) was not different (P = 0.14). However, 8 (35%) of 23 FLT3 ITD/+ cases also lacked a FLT3 WT allele (FLT3(ITD-R)) as determined by PCR and loss of heterozygosity. Thus, three genotypic groups were identified: normal FLT3(WT/WT), heterozygous FLT3(ITD/WT), and hemizygous FLT3(ITD/-). DFS and OS were significantly inferior for patients with FLT3(ITD/-) (P = 0.0017 and P = 0.0014, respectively). Although DFS and OS for FLT3(WT/WT) and FLT3(ITD/WT) groups did not differ (P = 0.32 and P = 0.98, respectively), OS of the FLT3(ITD/-) group was worse than the FLT3(WT/WT) (P = 0.0005) and FLT3(ITD/WT) (P = 0.008) groups. We propose a model in which FLT3(ITD/-) represents a dominant positive, gain-of-function mutation providing AML cells with a greater growth advantage compared with cells having the FLT3(WT/WT) or FLT3(ITD/WT) genotypes. In conclusion, we have identified the FLT3(ITD/-) genotype as an adverse prognostic factor in de novo AML with normal cytogenetics. A poor prognosis of the relatively young FLT3(ITD/-) adults (median age, 37 years), despite treatment with current dose-intensive regimens, suggests that new treatment modalities, such as therapy with a FLT3 tyrosine kinase inhibitor, are clearly needed for this group of patients.

Acute Disease↗
PubMed2006

In planta transient expression as a system for genetic and biochemical analyses of chlorophyll biosynthesis.

BACKGROUND: Mg chelatase is a multi-subunit enzyme that catalyses the first committed step of chlorophyll biosynthesis. Studies in higher plants and algae indicate that the Mg chelatase reaction product, Mg-protoporphyrin IX plays an essential role in nuclear-plastid interactions. A number of Mg chelatase mutants have been isolated from higher plants, including semi-dominant alleles of ChlI, the gene encoding the I subunit of the enzyme. To investigate the function of higher plant CHLI, bacterial orthologues have been engineered to carry analogous amino acid substitutions to the higher plant mutations and the phenotypes examined through in vitro characterization of heterologously produced proteins. Here, we demonstrate the utility of a transient expression system in Nicotiana benthamiana for rapidly assaying mutant variants of the maize CHLI protein in vivo. RESULTS: Transient expression of mutant maize ChlI alleles in N. benthamiana resulted in the formation of chlorotic lesions within 4 d of inoculation. Immunoblot analyses confirmed the accumulation of maize CHLI protein suggesting that the chlorosis observed resulted from an interaction between maize CHLI and endogenous components of the N. benthamiana chlorophyll biosynthetic pathway. On the basis of this assay, PCR-based cloning techniques were used to rapidly recombine polymorphisms present in the alleles studied allowing confirmation of causative lesions. A PCR-based mutagenesis was conducted and clones assayed by transient expression. A number of novel allelic variants of maize ZmChlI were generated and analyzed using this assay, demonstrating the utility of this technique for fine mapping. CONCLUSION: Transient expression provides a convenient, high-throughput, qualitative assay for functional variation in the CHLI protein. Furthermore, we suggest that the approach used here would be applicable to the analysis of other plastid-localized proteins where gain-of-function mutations will result in readily observable mutant phenotypes.

Journal Article↗
PubMed2005

The effect of GIRK2(wv) on neurite growth, protein expression, and viability in the CNS-derived neuronal cell line, CATH.A-differentiated.

Death occurs in the homozygous mutant mouse weaver among several classes of neuron in cerebellum and ventral midbrain, because these neurons carry a mutation in the G protein-gated inwardly rectifying potassium channel, Girk2. GIRK2 is expressed in all neuronal types killed by wv in cerebellum and midbrain as well as in neurons elsewhere that suffer lesser consequences. GIRK2(wv) affects neurons postnatally, after proliferation, at the time of final differentiation. To assess the impact of GIRK2(wv) on neuronal development and viability, we introduced cDNA encoding wild-type and mutant channels into a variant of a CNS derived catecholamine cell line (Cath.a) known as Cath.a-differentiated. When cultured in serum-free medium, Cath.a-differentiated cells cease proliferation and undergo morphological differentiation, growing long neurites. Cath.a-differentiated cells do not express endogenous Girk channels. Transfection of GIRK2(wv) resulted in the death of Cath.a-differentiated cells, in a cDNA-concentration dependent manner. The highest concentration of Girk2(wv) cDNA caused loss of about half the cells, the next highest concentration one-third, and the least had no effect on viability. However, even the lowest concentration resulted in disruption of neurite outgrowth and reduced the protein products of co-transfected genes. High concentrations of MK801, which prevent Na(+) influx through the mutant channel, prevented death induced by GIRK2(wv). Cell death and disruption of neurite outgrowth were counteracted in GIRK2(wv)-expressing cells by the presence of an unrelated inwardly rectifying potassium channel, Kir2.3. These results are consistent with wv being a gain-of-function mutation, causing disruption of cellular homeostasis by mechanisms such as increased Na(+) influx and chronic depolarization which may in turn result in an excessive metabolic burden on the cell.

Animals↗
PubMed2000

Type 2B von Willebrand's disease in thirteen individuals from five unrelated Australian families: phenotype and genotype correlations.

Type 2B von Willebrand's disease (VWD) is due to a qualitative defect in von Willebrand factor (VWF) in which there is an increased affinity for the platelet glycoprotein Ib-IX-V receptor complex. Spontaneous binding of type 2B VWF to platelets and subsequent clearance from the plasma is thought to account for the characteristic phenotype of type 2B VWD. These gain-of-function mutations are due to single amino substitutions that are clustered within the functionally important A1 domain of VWF. We describe 13 individuals from five unrelated families in Australia with type 2B VWD, report their phenotypic abnormalities, and delineate their causative mutations. We confirm that the mutation Arg543Trp is also particularly common among families with type 2B VWD in Australia.

Amino Acid Substitution↗
PubMed2007

PTPN22 620W allele is not associated with aplastic anemia.

The 1858C/T variant in PTPN22 imparts a gain of function mutation dysregulating T-cell stimulation and is associated with an array of autoimmune diseases. Using a case-control design, we compared the frequency of this polymorphism in 91 patients with acquired aplastic anemia to 132 ethnically matched controls. Representation of the PTPN22 variant was not significantly different between the two populations, suggesting that this gene polymorphism does not contribute to the etiology of aplastic anemia. Aplastic anemia thus joins a list of autoimmune diseases that commonly lack a major humoral disease component and do not associate with the PTPN22 variant.

Adolescent↗
PubMed1998

Quinidine sulfate therapy for the slow-channel congenital myasthenic syndrome.

The slow-channel congenital myasthenic syndrome (SCCMS) is caused by gain of function mutations in subunits of the end-plate acetylcholine receptor (AChR). The mutations prolong the opening episodes of the AChR channel, leading to a depolarization block and an end-plate myopathy. Because levels of quinidine sulfate attainable in clinical practice shorten the opening episodes of genetically engineered mutant SCCMS receptors in vitro, we tested the notion that the drug can be of benefit in SCCMS. We treated 6 SCCMS patients with quinidine sulfate in an open-label trial, using objective clinical measures of muscle strength and repetitive stimulation studies as end points. One patient became allergic to quinidine after 7 days. The remaining patients tolerated the drug well and after 30 days of continuous therapy showed statistically significant improvement in muscle strength and in decrement of the compound muscle action potential elicited by rapid rates of stimulation.

Action Potentials↗
PubMed2006

Novel approaches in the treatment of systemic mastocytosis.

In the absence of curative options, therapy for aggressive forms of systemic mastocytosis (SM) has relied in the use of cytoreductive agents, mainly interferon-alpha (IFN-alpha) and cladribine. However, responses are transient and only occur in a subset of patients. Gain-of-function mutations at codon 816 of the KIT protooncogene lead to constitutively active Kit receptor molecules, which are central to the pathogenesis of SM. Recent advances in the understanding of the molecular underpinnings of SM have led to the development of small molecules targeting mutant Kit tyrosine kinase isoforms that significantly have widened the range of therapeutic options for patients with SM. Some of these promising agents, such as dasatinib, AMN107, and PKC412, currently are under investigation in clinical trials whereas, others are at different stages of preclinical development. In addition, monoclonal antibodies directed to neoplastic mast cell-restricted surface antigens constitute a viable option for the treatment of SM that warrants further investigation.

Antibodies, Monoclonal↗
PubMed2005

Risk factors for thrombophilia in extrahepatic portal vein obstruction.

Scant information exists on the role of thrombophilia in extrahepatic portal vein obstruction (EHPVO). We studied 65 patients with EHPVO, 500 with deep vein thrombosis (DVT) of the lower limbs, and 700 healthy controls referred for thrombophilia screening, including the search for gain-of-function mutations in genes encoding coagulation factor V (factor V Leiden) and prothrombin (prothrombin G20210A); antithrombin, protein C, and protein S deficiency; and hyperhomocysteinemia. At least one abnormality in the thrombophilia screening was found in 40% of patients with either EHPVO or lower limb DVT and in 13% of controls, for odds ratios of 4.0 (95% CI, 2.3-7.0) and 4.4 (95% CI, 3.3-5.9), respectively. Statistically significant associations with EHPVO were observed for the prothrombin G20210A mutation (odds ratio, 8.1; 95% CI, 3.8-17.5) and the deficiencies of antithrombin, protein C, or protein S taken together (odds ratio, 4.5; 95% CI, 1.1-18.0). The odds ratio for the prothrombin G20210A was approximately twice that for lower limb DVT. Patients with factor V Leiden had an odds ratio for EHPVO of 0.8 (95% CI, 0.1-6.4) and for lower limb DVT of 7.5 (95% CI, 4.4-13.0). The odds ratio for EHPVO in patients with hyperhomocysteinemia was 2.0 (95% CI, 0.9-4.9). At variance with lower limb DVT, oral contraceptive use was not associated with an increased risk of EHPVO. Myeloproliferative disorders were diagnosed in 35% of patients with EHPVO. In conclusion, the risk for EHPVO is increased in the presence of thrombophilia resulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins, but not from factor V Leiden.

Adolescent↗
PubMed2006

Helicobacter pylori CagA -- a bacterial intruder conspiring gastric carcinogenesis.

Infection with cagA-positive Helicobacter pylori (H. pylori) is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is delivered from the bacterium into the cytoplasm of the bacterium-attached gastric epithelial cell via the type-IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, translocated CagA functions as a scaffolding adaptor that interacts with a number of host proteins involved in cell signaling in both tyrosine phosphorylation-dependent and -independent manners. Of special interest is the interaction of CagA with the SHP-2 tyrosine phosphatase, of which gain-of-function mutations have recently been found in human malignancies. Through the complex formation, SHP-2 is catalytically activated and induces morphological transformation that is associated with increased cell motility. In addition to the perturbation of intracellular signaling, CagA disrupts the apical junctional complex that regulates the cell-cell contact and maintains the integrity of the epithelial structure. These CagA activities may collectively cause cellular dysfunctions that promote accumulation of multiple genetic changes involved in malignant transformation. Further elucidation of host cell signaling targeted by CagA should provide a new paradigm for 'bacterial carcinogenesis' and also give insights into general understanding of inflammation-mediated cancers. Clinically, detailed studies on the relationship between structural diversity and degree of pathogenic activity of CagA should make it possible to identify a high-risk group for gastric carcinoma among H. pylori-infected populations through cagA genotyping.

Adenocarcinoma↗
PubMed2003

Neural expression of the Huntington's disease gene as a chordate evolutionary novelty.

Huntington's disease is a progressive neuro-degenerative disorder in humans, which is scharacterized by onset of dementia, muscular ataxia, and death. Huntington's disease is caused by the expansion of the polyglutamine (polyQ) tract in the N-terminus of the HD protein (Huntingtin). CAG expansion is a dominant gain of function mutation that affects striated neurons in the brain (Cattaneo, 2003, News Physiol Sci 18:34). The evolutionary origins of the vertebrate Hd gene are not well understood. In order to address the evolutionary history of the Hd gene, we have cloned and characterized the expression of the Hd gene in two invertebrate deuterostomes, an echinoderm and an ascidian, and have examined the expression patterns in a phylogenetic context. Echinoderms are basal deuterostomes and ascidians are basal chordates; both are useful for understanding the origins of and evolutionary trends in genes important in vertebrates such as the Huntigton's disease gene. Expression of Hd RNA is detected at all stages of development in both the echinoderm and ascidian studied. In the echinoderm Heliocidaris erythrogramma, Hd is expressed in coelomic mesodermal tissue derivatives, but not in the central nervous system. In the ascidian Halocynthia roretzi expression is located in both mesoderm and nervous tissue. We suggest that the primitive deuterostome expression pattern is not neural. Thus, neural expression of the Hd gene in deuterostomes may be a novel feature of the chordate lineage, and the original role(s) of HD in deuterostomes may have been non-neural.

Amino Acid Sequence↗
PubMed2005

Gastric GI stromal tumors (GISTs): the role of surgery in the era of targeted therapy.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm arising in the stomach. These tumors were previously classified as smooth muscle tumors, but in recent years it has become clear that they are clinically, pathologically, and molecularly distinct from other tumors and are much more common than previously appreciated. Historically, patients with primary localized or advanced GIST have been managed surgically, as there was no proven role of other treatment modalities such as radiation or chemotherapy. However, the field of GIST was revolutionized with the 1998 discovery that the vast majority of these tumors have oncogenic gain-of-function mutations of the KIT receptor tyrosine kinase. Follow-up studies have confirmed that KIT is both a useful diagnostic marker and an excellent therapeutic target. Imatinib, an inhibitor of KIT kinase activity, is now the standard front-line therapy for patients with advanced GIST. In this review, we discuss pathological and molecular features of gastric GISTs and review the historic and current roles of surgery in the treatment of patients with primary or metastatic GIST. The importance of a multi-disciplinary approach using both surgery and imatinib therapy is emphasized.

Benzamides↗
PubMed1995

Assignment of the transcription factor GATA4 gene to human chromosome 8 and mouse chromosome 14: Gata4 is a candidate gene for Ds (disorganization).

We report the mapping of the human and mouse genes for transcription factor GATA-4, a newly identified member of DNA-binding proteins involved in lineage determination. The human GATA4 gene was assigned to the short arm of human chromosome 8 using genomic DNAs from human-rodent somatic cell hybrid lines. Southern blot analyses indicated the presence of a human-specific 7.6-kb fragment that was observed only in DNA from the hybrid cells containing human chromosome 8 or the proximal region of its short arm. The mouse Gata4 gene was mapped to chromosome 14, closely linked to Clu (clusterin), using genomic DNAs from a (C57BL/6J x Mus spretus)F1 x M. spretus backcross. This mapping assignment places the Gata4 gene in the vicinity of the mouse Ds (disorganization) locus, a dominant gain-of-function mutation affecting embryonic development. We speculate that Ds is caused by a mutation in the Gata4 gene, ectopic expression of GATA-4, or a mutation in another lineage determination gene closely linked to Gata4.

Abnormalities, Multiple↗
PubMed1995

A single amino acid change in a pathway-specific transcription factor results in differing degrees of constitutivity, hyperinducibility and derepression of several structural genes.

unYc462 is a gain-of-function mutation in the purine catabolism positive regulatory gene of Aspergillus nidulans. This allele leads to a constitutive, hyperinducible and derepressed expression of a least three genes controlled by uaY, and this occurs at different levels depending on the target gene. The uaYc462 allele was mapped physically in relation to known loss-of-function alleles and sequenced. uaYc462 is a one-base change in codon 222, resulting in a serine to leucine change. We propose that this mutation maps in a functional domain involved, directly or indirectly, in the interaction of UaY with other components of the transcriptional apparatus. A sequence similar to the motif surrounding serine 222 may play similar roles in the PPR1 and ADR1 proteins of Saccharomyces cerevisiae.

Amino Acid Sequence↗
PubMed1999

The role of copper in neurodegenerative disease.

Copper is an essential trace metal which plays a fundamental role in the biochemistry of the human nervous system. Menkes disease and Wilson disease are inherited disorders of copper metabolism and the dramatic neurodegenerative phenotypes of these two diseases underscore the essential nature of copper in nervous system development as well as the toxicity of this metal when neuronal copper homeostasis is perturbed. Ceruloplasmin contains 95% of the copper found in human plasma and inherited loss of this essential ferroxidase is associated with progressive neurodegeneration of the retina and basal ganglia. Gain-of-function mutations in the cytosolic copper enzyme superoxide dismutase result in the motor neuron degeneration of amyotrophic lateral sclerosis and current evidence suggests a direct pathogenic role for copper in this process. Recent studies have also implicated copper in the pathogenesis of neuronal injury in Alzheimer's disease and the prion-mediated encephalopathies, suggesting that further elucidation of the mechanisms of copper trafficking and metabolism within the nervous system will be of direct relevance to our understanding of the pathophysiology and treatment of neurodegenerative disease.

Adenosine Triphosphatases↗
PubMed1995

Fibrodysplasia ossificans progressiva: still turning into wood after 300 years?

Fibrodysplasia ossificans progressiva (FOP), a rare autosomal dominant disorder, is characterized by symmetrical congenital skeletal abnormalities and progressive heterotopic ossification of the connective tissues. At present, more than 300 years after the first report by Patin in 1648 in which he described the woman who "turned to wood", its pathogenesis remains largely unknown and its therapy is limited to symptom-modifying trials. However, significant progress has been recently made and new data on the molecular organization and regulation of normal and disordered bone induction are likely to lead to a more specific therapy. FOP is believed to be a genetic disorder characterized by a disturbed expression of the endochondral osteogenesis programme, and the remarkable "clues from the fly" reported by Kaplan et al. [8] in 1990 suggest a gain-of-function mutation in the genetic regulation of bone morphogenetic proteins.

Bone Morphogenetic Proteins↗