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Lethal Form (lethal + form)
Selected AbstractsA Novel Early Onset Lethal Form of Catecholaminergic Polymorphic Ventricular Tachycardia Maps to Chromosome 7p14-p22JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2007Ph.D., ZAHURUL A. BHUIYAN M.D. Introduction: Previously, autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT [1]) was mapped to chromosome 1q42,43 with identification of pathogenic mutations in RYR2. Autosomal recessive CPVT (2) was mapped to chromosome 1p13,21, leading to the identification of mutations in CASQ2. In this study, we aimed to elucidate clinical phenotypes of a new variant of CPVT (3) in an inbred Arab family and also delineate the chromosomal location of the gene causing CPVT (3). Methods and Results: In a highly inbred family, clinical symptoms of CPVT appeared early in childhood (7,12 years) and in three of the four cases, the first appearance of symptoms turned into a fatal outcome. Parents of the affected children were first-degree cousins and without any symptoms. Segregation analysis suggested an autosomal recessive inheritance. A genome-wide search using polymorphic DNA markers mapped the disease locus to a 25-Mb interval on chromosome 7p14-p22. A maximal multipoint LOD score of 3.17 was obtained at marker D7S493. Sequencing of putative candidate genes, SP4, NPY, FKBP9, FKBP14, PDE1C, and TBX20, in and around this locus, did not reveal any mutation. Conclusions: We have identified a novel highly malignant autosomal recessive form of CPVT and mapped this disorder to a 25-Mb interval on chromosome 7p14-p22. [source] Sunlight ultraviolet irradiation and BRAF V600 mutagenesis in human melanoma,HUMAN MUTATION, Issue 8 2008Ahmad Besaratinia Abstract The incidence of melanoma, the most lethal form of skin cancer, continues to increase in the Western world. In addition to genetic alterations in high- and low-susceptibility genes identified for melanoma, somatic mutations in BRAF gene occur frequently in human melanoma and are distinctively linked to sun exposure. Of significance is a single hotspot codon, i.e., BRAF V600, wherein up to 92% of all mutations arise. Recent work in our laboratory has demonstrated that solar ultraviolet (UV) irradiation triggers mutagenesis through induction of various DNA lesions, many of which capable of producing similar types of mutations, as those seen in BRAF V600 variants in human melanoma. In this review article, we have discussed application of "DNA damage-targeted mutagenicity" of solar UV-irradiation for determining the mechanistic involvement of sunlight UV in BRAF V600 mutagenesis in human melanoma. We envision that establishing "DNA-damage derived mutagenesis" in this exceptionally unique target gene may resolve the underlying mechanism(s) of melanoma-genesis, thus helping define preventive and therapeutic measures against this malignant disease. Hum Mutat 0, 1,9, 2008. © 2008, Wiley-Liss, Inc. [source] Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantumJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 13 2010Santhosh Kannan Venkatesan Abstract Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol-redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9-aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9-aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Germline mosaicism in keratitis,ichthyosis,deafness syndrome: pre-natal diagnosis in a familial lethal formCLINICAL GENETICS, Issue 6 2010E Sbidian Sbidian E, Feldmann D, Bengoa J, Fraitag S, Abadie V, de Prost Y, Bodemer C, Hadj-Rabia S. Germline mosaicism in keratitis,ichthyosis,deafness syndrome: pre-natal diagnosis in a familial lethal form. Keratitis,ichthyosis,deafness (KID) syndrome is an autosomal dominant congenital ectodermal defect characterized by the association of skin lesions, hearing loss and keratitis. Most of the cases appear to be sporadic. KID syndrome is mostly related to mutations of GJB2 gene encoding connexin-26. Recently, a lethal form of the disease during the first year of life has been reported in two unrelated Caucasian patients. This rare lethal form is caused by the G45E mutation of GJB2 gene. We here report the first pre-natal molecular genetic diagnosis of the lethal form of KID syndrome relating to a G45E mutation. In the same family, the occurrence of this condition in three other siblings born to African non-consanguineous healthy parents lead to perform pre-natal diagnosis for this last pregnancy. Molecular analysis confirms the diagnosis of the lethal form of KID for the fetus. These results establish the role of germline mosaicism in KID syndrome and warrant careful genetic counseling. Furthermore, analysis of our cases and the literature allowed us to define a characteristic severe neonatal phenotype including facial dysmorphy, severe cornification with massive focal hyperkeratosis of the skin with erythroderma, dystrophic nails, complete atrichia and absence of foreskin. [source] Lactate Detection by MRS in Mitochondrial Encephalopathy: Optimization of Technical ParametersJOURNAL OF NEUROIMAGING, Issue 1 2008Antônio José da Rocha MD ABSTRACT Mitochondriopathies are a heterogeneous group of diseases with variable phenotypic presentation, which can range from subclinical to lethal forms. They are related either to DNA mutations or nuclear-encoded mitochondrial genes that affect the integrity and function of these organelles, compromising adenosine triphosphate (ATP) synthesis. Magnetic resonance (MR) is the most important imaging technique to detect structural and metabolic brain abnormalities in mitochondriopathies, although in some cases these studies may present normal results, or the identified brain abnormalities may be nonspecific. Magnetic resonance spectroscopy (MRS) enables the detection of high cerebral lactate levels, even when the brain has normal appearance by conventional MR scans. MRS is a useful tool for the diagnosis of mitochondriopathies, but must be correlated with clinical, neurophysiological, biochemical, histological, and molecular data to corroborate the diagnosis. Our aim is to clarify the most relevant issues related to the use of MRS in order to optimize its technical parameters, improving its use in the diagnosis of mitochondriopathies, which is often a challenge. [source] | |||||||||||||