Genetic Lesions (genetic + lesion)

Distribution by Scientific Domains


Selected Abstracts


Relevance of Ras gene mutations in the context of the molecular heterogeneity of multiple myeloma

HEMATOLOGICAL ONCOLOGY, Issue 1 2007
Daniela Intini
Abstract Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). Here, we report a mutation analysis of N- and K- Ras genes in purified plasma cell populations from a panel of 81 newly diagnosed MM patients stratified according to the most frequent genetic and molecular features associated with the neoplasia. Ras gene mutations, mostly involving the N- Ras gene, were detected in 20% of the patients. Ras mutations did not correlate with the presence of chromosome 13q deletion, trisomy of chromosome 11, 1q amplification or hyperdiploidy. In addition, despite an appreciable association with tumours overexpressing Cyclin D1, Ras mutations did not correlate at significant levels with any of the proposed groups in the TC classification, based on the presence of the major IgH chromosomal translocations and expression of Cyclin D genes. Finally, transcription analyses revealed the presence of differentially expressed transcripts in human multiple myeloma cell lines carrying the Ras gene mutations but not in primary tumours. Overall, these data suggest that Ras gene mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities. Copyright © 2006 John Wiley & Sons, Ltd. [source]


P53 mutations in stromal fibroblasts sensitize tumors against chemotherapy

INTERNATIONAL JOURNAL OF CANCER, Issue 4 2008
Daniel Lafkas
Abstract The efficacy of chemotherapy is usually viewed as the outcome of cancer-cell-autonomous processes while the contribution of stroma is being overseen. Here we show that p53 mutations in stromal fibroblasts, a genetic lesion that is detectable in primary breast, prostate and probably other cancers, while they accelerate tumorigenesis they also sensitize tumours against conventional chemotherapy by doxorubicin and cis -platinum. The mechanism by which p53 of stromal fibroblasts affects the response of a tumour against chemotherapy is likely to involve the induction of senescence in the fibroblasts which in turns results in the production of growth factors acting onto the cancer cells by paracrine mechanisms. Our findings identify stromal fibroblasts as important modulators of the efficacy of anticancer therapy. © 2008 Wiley-Liss, Inc. [source]


Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti

MOLECULAR MICROBIOLOGY, Issue 3 2002
Alexander S. Pym
Summary Although large human populations have been safely immunized against tuberculosis with two live vaccines, Mycobacterium bovis BCG or Mycobacterium microti, the vole bacillus, the molecular basis for the avirulence of these vaccine strains remains unknown. Comparative genomics has identified a series of chromosomal deletions common to both virulent and avirulent species but only a single locus, RD1, that has been deleted from M. bovis BCG and M. microti. Restoration of RD1, by gene knock-in, resulted in a marked change in colonial morphology towards that of virulent tubercle bacilli. Three RD1-encoded proteins were localized in the cell wall, and two of them, the immunodominant T-cell antigens ESAT-6 and CFP-10, were also found in culture supernatants. The BCG::RD1 and M. microti::RD1 knock-ins grew more vigorously than controls in immunodeficient mice, inducing extensive splenomegaly and granuloma formation. Increased persistence and partial reversal of attenuation were observed when immunocompetent mice were infected with the BCG::RD1 knock-in, whereas BCG controls were cleared. Knocking-in five other RD loci did not affect the virulence of BCG. This study describes a genetic lesion that contributes to safety and opens new avenues for vaccine development. [source]


Losing B cell identity

BIOESSAYS, Issue 3 2008
Sebastian Carotta
The transcription factor Pax5 is essential for the initial commitment of hematopoietic progenitors to the B cell lineage. Recently, our understanding of the lineage commitment process has been extended with the finding that Pax5 is also continuously required throughout B cell development to reinforce commitment, as inactivation of Pax5 in mature B cells results in their de-differentiation to a progenitor stage that is capable of multi-lineage potential.1 The reliance of B cell identity on a single gene is not without its problems as the loss of Pax5 results in B cell malignancies in mouse models and mutation in human PAX5 is the most-common genetic lesion in acute lymphoblastic leukemia. BioEssays 30:203,207, 2008. © 2008 Wiley Periodicals, Inc. [source]


The tight relationship between papillary thyroid cancer, autoimmunity and inflammation: clinical and molecular studies

CLINICAL ENDOCRINOLOGY, Issue 5 2010
Marina Muzza
Summary Objective, The recent concept that oncogenes responsible for thyroid neoplastic transformation are able to elicit an inflammatory protumourigenic microenvironment raises interest in further studies on papillary thyroid cancer (PTC) associated with thyroid autoimmunity. Patients, The clinical and molecular features, and the expression of inflammation-related genes, were investigated in a large series of PTCs with and without associated thyroiditis (groups A, n = 128 and B, n = 215). Results, The two groups did not show significant differences in clinical and prognostic features, whereas they harboured a significantly different genetic background (P = 0·001), with RET/PTC1 being more represented in PTCs associated with autoimmunity, and BRAFV600E in patients with PTC alone. A RET/PTC rearrangement was also found in 41% of non-neoplastic thyroiditis tissues, contralateral to tumours harbouring either RET/PTC or BRAF mutations. The expression of genes encoding CCL20, CXCL8 and l -selectin was significantly higher in PTC specimens (either with RET/PTC, BRAFV600E or unknown genetic lesion) compared with normal thyroid samples. On the contrary, thyroiditis showed l -selectin expression levels even higher than PTCs, but CCL20 and CXCL8 levels comparable with normal tissues. Conclusions, The present data extend the knowledge about the tight relationships among oncogenes, thyroiditis and thyroid cancer. A different genetic background among PTCs with and without associated autoimmunity has been firstly demonstrated. The strong association between RET/PTC1 and thyroiditis points to a critical role of this oncoprotein in the modulation of the autoimmune response. Moreover, preliminary expression studies, indicating enhanced expression of inflammatory molecules in PTCs, suggest a proinflammatory, nonautoimmune relationship between thyroiditis and thyroid cancer. [source]


Neonatal salt-wasting and 11 ,-hydroxylase deficiency in a child carrying a homozygous deletion hybrid CYP11B2 (aldosterone synthase),CYP11B1 (11 ,-hydroxylase)

CLINICAL GENETICS, Issue 3 2004
B Ezquieta
This article reports the case of a boy diagnosed at 1.8 years of age with congenital adrenal hyperplasia due to 11 ,-hydroxylase deficiency. The patient showed salt-wasting episodes during the neonatal period. On molecular analysis, a homozygous deletion hybrid (CYP11B2,CYP11B1) involving the CYP11B locus at 8q24.3 was found. Southern blot analysis showed the break point of the chimera gene to be located before intron 5; sequence analysis identified it at exon 4 between codons 202 and 248. This CYP11B2(5,)/B1(3,) hybrid should lack aldosterone synthase activity (due to the CYP11B1 residues at exons 5 and 6), and the enzyme it codes for should not be promoted by adrenocorticotropic hormone (ACTH) (CYP11B2 promoter sequences). The patient phenotype , neonatal salt-wasting and 11 ,-hydroxylase deficiency , is in agreement with this hybrid structure. This is the first time a homozygous deletion hybrid generated by unequal crossover has been described in exon 4. This genetic lesion appears to be the reciprocal product from the recombination event that causes glucocorticoid-remediable aldosteronism, a duplication dominant allele (CYP11B2,CYP11B1/B2,CYP11B1) coding for additional aldosterone synthase activity regulated by ACTH. The clinical presentation of the condition in this patient contributes to the in vivo understanding of the regulation of this complex locus in which two ,duplicated' genes have evolved different regulatory and enzymatic activities involved in mineralocorticoid and glucocorticoid synthesis in the adrenal glands. The fact that this allele was first predicted and has now been documented clinically and molecularly in vivo is particularly noteworthy. [source]


Molecular genetics of Xeroderma pigmentosum variant

EXPERIMENTAL DERMATOLOGY, Issue 5 2003
Alexei Gratchev
Skin abnormalities result from an inability to repair UV-damaged DNA because of defects in the nucleotide excision repair (NER) machinery. Xeroderma pigmentosum is genetically heterogeneous and is classified into seven complementation groups (XPA-XPG) that correspond to genetic alterations in one of seven genes involved in NER. The variant type of XP (XPV), first described in 1970 by Ernst G. Jung as ,pigmented xerodermoid', is caused by defects in the post replication repair machinery while NER is not impaired. Identification of the XPV gene was only achieved in 1999 by biochemical purification and sequencing of a protein from HeLa cell extracts complementing the PRR defect in XPV cells. The XPV protein, polymerase (pol),, represents a novel member of the Y family of bypass DNA polymerases that facilitate DNA translesion synthesis. The major function of pol, is to allow DNA translesion synthesis of UV-induced TT-dimers in an error-free manner; it also possesses the capability to bypass other DNA lesions in an error-prone manner. Xeroderma pigmentosum V is caused by molecular alterations in the POLH gene, located on chromosome 6p21.1,6p12. Affected individuals are homozygous or compound heterozygous for a spectrum of genetic lesions, including nonsense mutations, deletions or insertions, confirming the autosomal recessive nature of the condition. Identification of POLH as the XPV gene provides an important instrument for improving molecular diagnostics in XPV families. [source]


Molecular genetics of pseudoxanthoma elasticum

EXPERIMENTAL DERMATOLOGY, Issue 4 2001
F. Ringpfeil
Abstract: Pseudoxanthoma elasticum (PXE), a systemic heritable connective tissue disorder, is characterized by progressive calcification of elastic structures in the skin, the eyes and the cardiovascular system, with considerable intra- and interfamilial phenotypic variability. Recently, underlying genetic defects have been identified in the ABCC6 gene, which resides on the chromosomal locus 16p13.1 and encodes the MRP6 protein, a member of the ATP-binding cassette (ABC) family of proteins. The affected individuals are homozygous or compound heterozygous for a spectrum of genetic lesions, including nonsense and missense mutations, or deletions and splice-site alterations, confirming the autosomal recessive nature of this condition. Analysis of the deduced primary sequence suggests that MRP6 is a transmembrane transporter, but its function has not been delineated yet. Surprisingly, however, MRP6 is expressed primarily, if not exclusively, in the liver and the kidneys, suggesting that PXE may be a primary metabolic disorder with secondary involvement of elastic fibers. Identification of mutations in the ABCC6 gene in PXE provides a means for prenatal and presymptomatic testing in families at risk for recurrence. DNA-based analyses will also identify heterozygous carriers who may be at risk for development of limited manifestations of the disease as a result of compounding genetic factors and/or environmental modifiers. [source]


Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology

HEMATOLOGICAL ONCOLOGY, Issue 4 2008
Efsevia Vakiani
Abstract B-cell post-transplant lymphoproliferative disorders (PTLD) are classified as early lesions, polymorphic lymphomas (P-PTLD) and monomorphic lymphomas (M-PTLD). These morphologic categories are thought to reflect a biologic continuum, although supporting genetic data are lacking. To gain better insights into PTLD pathogenesis, we characterized the phenotypes, immunoglobulin (Ig) gene alterations and non-Ig gene (BCL6, RhoH/TTF, c-MYC, PAX5, CIITA, BCL7A, PIM1) mutations of 21 PTLD, including an IM-like lesion, 8 P-PTLD and 12 M-PTLD. Gene expression profile analysis was also performed in 12 cases. All PTLD with clonal Ig rearrangements showed evidence of germinal centre (GC) transit based on the analysis of Ig and BCL6 gene mutations, and 74% had a non-GC phenotype (BCL6,±,MUM1+). Although surface Ig abnormalities were seen in 6/19 (32%) PTLD, only three showed ,crippling' Ig mutations indicating other etiologies for loss of the B-cell receptor. Aberrant somatic hypermutation (ASHM) was almost exclusively observed in M-PTLD (8/12 vs. 1/8 P-PTLD) and all three recurrent cases analysed showed additional mutations in genes targeted by ASHM. Gene expression analysis showed distinct clustering of PTLD compared to B-cell non-Hodgkin lymphomas (B-NHL) without segregation of P-PTLD from non-GC M-PTLD or EBV+ from EBV, PTLD. The gene expression pattern of PTLD appeared more related to that of memory and activated B-cells. Together, our results suggest that PTLD represent a distinct type of B-NHL deriving from an antigen experienced B-cell, whose evolution is associated with accrual of genetic lesions. Copyright © 2008 John Wiley & Sons, Ltd. [source]


Human disease resulting from gene mutations that interfere with appropriate nuclear factor-,B activation

IMMUNOLOGICAL REVIEWS, Issue 1 2005
Jordan S. Orange
Summary:, The nuclear factor (NF)-,B family of transcription factors serves vital roles in a wide array of cell functions. An increasing number of human genetic lesions that result in defined disease entities are linked to inappropriate activation of NF-,B. The resulting aberrant NF-,B function can lead to cellular defects that ultimately impair normal developmental processes, host immune defenses, or both. Molecular defects that lie upstream in cell-signaling pathways and rely upon NF-,B activation tend to give a more specific phenotype, whereas those closer to the actual NF-,B proteins have broader defects. A detailed study of these diseases can provide insight into the biochemistry of NF-,B activation as well as the role of NF-,B in human health. [source]


Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway

INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2002
D. A. LAMMAS
Summary Patients with genetic lesions in the Type-1 cytokine/cytokine receptor pathway exhibit a selective susceptibility to severe infections with poorly pathogenic mycobacteria and non-typhi salmonella spp. These experiments of nature demonstrate that IL-12-dependent IFN, production is critical for granuloma formation and therefore host immunity against such pathogens. The essential role of granuloma formation for protective immunity to these organisms is emphasized by the differing granuloma forming capabilities and resultant clinical sequelae observed in these patients which seems to reflect their ability to produce or respond to IFN, (Fig. 9). At one pole of this spectrum, represented by the complete IFN,R1/2 deficient patients, there is a complete absence of mature granuloma formation, whereas with the less severe mutations (i.e. partial IFN,R1/2, complete IL-12p40 and complete IL-12R,1 deficiency), granuloma formation is very heterogenous with wide variations in composition being observed. This suggests that in the latter individuals, who produce partial but suboptimal IFN, responses, other influences, including pathogen virulence and host genotype may also affect the type and scale of the cellular response elicited. Figure 9. ,Spectrum of genetic susceptibility to intracellular bacteria. At one pole of this spectrum complete IFN,R deficiencies are found; at the other pole are healthy resistant individuals. Partial IFN,R1 deficiencies, and complete IL-12R,1 and IL-12p40 deficiencies can be positioned in between, albeit closer to the former end of the spectrum, with clinical outcome also depending on pathogen virulence and host compensatory immune mechanism(s). Abbreviations: IFN,R , interferon gamma receptor, IL-12R,1 , interleukin 12 receptor-1 (modified from Ottenhoff et al. (1998)). [source]


Hereditary Degenerative Retinopathies: Optimism for Somatic Gene Therapy

IUBMB LIFE, Issue 6 2000
Barkur S. Shastry
Abstract Retinitis pigmentosa comprises a large and exceptionally heterogeneous group of hereditary disorders of the retina. As a result of an extensive investigation around the world, primary genetic lesions have been described in many genes. Some of these genes encode enzymes that are involved in the signal transduction pathway. On the basis of in vitro functional assays and standard transgenic and knock-out experiments, it has been proposed that normal cell functions are disrupted because of an abnormal protein-folding and metabolic errors or structural defects in the membrane. This ultimately leads to a gene-mediated cell death known as apoptosis. Various gene transfer approaches using mouse models further suggest that the degeneration can be rescued to some extent. Although many questions remain to be answered, investigations during the last 10 years have enormously increased our understanding of this exceptionally heterogeneous disorder and give hope for an effective gene therapy and a possible cure. [source]


Thrombosis in inherited factor VII deficiency

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2003
G. Mariani
Summary., Thrombosis in congenital factor (F) VII deficiency was investigated through extensive phenotypic and molecular-genetic studies. Patients with a history of thrombosis among 514 entries in the FVII Deficiency Study Group database were evaluated. Thrombotic events were arterial in one case, disseminated intravascular coagulation in another and venous in seven. Gene mutations were characterized in eight patients: three were homozygous, three compound heterozygous and two heterozygous. FXa and IIa generation assays were consistent with the genetic lesions. One patient was heterozygous for the FV Leiden and one for the FIIG20210A mutation. In seven patients, surgical interventions and/or replacement therapies had a close temporal relationship with thrombosis, while in the remaining, events were apparently spontaneous. Thromboses were not associated with any specific age, phenotype, mutation zygosity or thrombophilic abnormalities. In particular, severe FVII deficiency did not seem to offer protection from strong thrombosis risk factors such as surgery and replacement therapy. [source]


Prader,Willi syndrome and Angelman syndrome,

AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 3 2010
Karin Buiting
Abstract Prader,Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurogenetic disorders in which imprinted genes on the proximal long arm of chromosome 15 are affected. Although the SNORD116 gene cluster has become a prime candidate for PWS, it cannot be excluded that other paternally expressed genes in the chromosomal region 15q11q13 contribute to the full phenotype. AS is caused by a deficiency of the UBE3A gene, which in the brain is expressed from the maternal allele only. The most frequent genetic lesions in both disorders are a de novo deletion of the chromosomal region 15q11q13, uniparental disomy 15, an imprinting defect or, in the case of AS, a mutation of the UBE3A gene. Microdeletions in a small number of patients with PWS and AS have led to the identification of the chromosome 15 imprinting center (IC). The IC consists of two critical elements, which act in cis to regulate imprinting in the whole chromosome 15q11q13 imprinted domain. © 2010 Wiley-Liss, Inc. [source]


Roles of bone morphogenetic protein signaling and its antagonism in holoprosencephaly,

AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010
John Klingensmith
Abstract Holoprosencephaly (HPE) is the most common malformation of the forebrain, resulting from a failure to completely septate the left and right hemispheres at the rostral end of the neural tube. Because of the tissue interactions that drive head development, these forebrain defects are typically accompanied by midline deficiencies of craniofacial structures. Early events in setting up tissue precursors of the head, as well as later interactions between these tissues, are critical for normal head formation. Defects in either process can result in HPE. Signaling by bone morphogenetic proteins (BMPs), a family of secreted cytokines, generally plays negative roles in early stages of head formation, and thus must be attenuated in multiple contexts to ensure proper forebrain and craniofacial development. Chordin and Noggin are endogenous, extracellular antagonists of BMP signaling that promote the normal organization of the forebrain and face. Mouse mutants with reduced levels of both factors display mutant phenotypes remarkably analogous to the range of malformations seen in human HPE sequence. Chordin and Noggin function in part by antagonizing the inhibitory effects of BMP signaling on the Sonic hedgehog and Nodal pathways, genetic lesions in each being associated with human HPE. Study of Chordin;Noggin mutant mice is helping us to understand the molecular, cellular, and genetic pathogenesis of HPE and associated malformations. © 2010 Wiley-Liss, Inc. [source]