65 research outputs found

    Susceptibility genes in the pathogenesis of murine lupus

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    Systemic lupus erythematosus (SLE) is the paradigm of a multisystem autoimmune disease in which genetic factors strongly influence susceptibility. Through genome scans and congenic dissection, numerous loci associated with lupus susceptibility have been defined and the complexity of the inheritance of this disease has been revealed. In this review, we provide a brief description of animal models of SLE, both spontaneous models and synthetic models, with an emphasis on the B6 congenic model derived from analyses of the NZM2410 strain. A hypothetical model of disease progression that organizes many of the identified SLE susceptibility loci in three distinct biological pathways that interact to mediate disease pathogenesis is also described. We finally discuss our recent fine mapping analysis, which revealed a cluster of loci that actually comprise the Sle1 locus

    Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome

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    Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation

    Genetic aspects of vascular malformations

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    Vascular malformations are comprised of a variety of developmental defects of the vasculature. Typi- cally sporadic in nature, they can sometimes occur as incompletely penetrant, inherited traits. The ge- netic bases of several of these anomalies have been identified, and are described in this review. This has had a hugely beneficial impact in terms of the pre- cise diagnosis and appropriate, effective treatment of different disease entities; it has also revealed poten- tial therapeutic targets for the future. The advances made thus far, however, are largely confined to the rare, familial forms, and much remains to be un- covered about the genes that mediate common spo- radic versions of vascular malformations. Moreover, the pathogenic pathways and molecular mechanisms by which the aberrant genes cause these defined, of- ten heterogeneous lesions, remain to be thoroughly dissected. Previous studies have largely focused on the analysis of blood samples, as these are more ac- cessible. Further progress in identifying the somat- ic events that cause sporadic lesions or locally ex- acerbate the pathogenic effects of germline-het- erozygous mutant alleles will require the additional assessment of irregularities of gene expression and function at the level of lesion-derived tissue

    From germline towards somatic mutations in the pathophysiology of vascular anomalies

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    The localized structural abnormalities that arise during vasculogenesis, angiogenesis and lymphangiogenesis, the developmental processes which give rise to the adult vasculature, are collectively termed vascular anomalies. The last 2 years have seen an explosion of studies that underscore paradominant inheritance, the combination of inherited changes with somatic second-hits to the same genes, as underlying rare familial forms. Moreover, local, somatic genetic defects that cause some of the common sporadic forms of these malformations have been unraveled. This highlights the importance of assessing for tissue-based genetic changes, especially acquired genetic changes, as possible pathophysiological causes, which have been largely overlooked except in the area of cancer research. Large-scale somatic screens will therefore be essential in uncovering the nature and prevalence of such changes, and their downstream effects. The identification of disease genes combined with exhaustive, precise clinical delineations of the entire spectra of associated phenotypes guides better management and genetic counseling. Such a synthesis of information on functional and phenotypic effects will enable us to make and use animal models to test less invasive, targeted, perhaps locally administered, biological therapies

    TIE2 (TEK) and venous malformation

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    Implication of T Helper Cytokines in Contact Dermatitis and Atopic Dermatitis

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    Purpose of review Cytokines play a key role in lesion development in inflammatory skin diseases such as contact dermatitis and atopic dermatitis and are of great interest as therapeutic targets. This is reflected in the increasing number of clinical studies and case reports as well as preclinical mouse models that provide substantial data on the participation of cytokines in these pathologies. In this review, we provide a detailed and comprehensive account of the advances in the field. Recent results The importance and therapeutic potential of Th2 cytokines in allergic contact dermatitis (ACD) and atopic dermatitis (AD) are well documented. Recent results have added another member, IL-24, to the list of key players in both diseases. In addition, IL-9, which is associated with Th9 cells, has been found to be strongly increased in ACD patients, opening up another promising new avenue. Summary In this review, we describe the expression and role of Th cytokines in skin inflammatory disorders, based on mouse models and existing therapy, focusing on cytokines associated with different subpopulations of T helper cells

    Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact.

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    One reason why some patients experience recurrent disease after a curative-intent treatment might be the persistence of residual tumor cells, called minimal residual disease (MRD). MRD cannot be identified by standard radiological exams or clinical evaluation. Tumor-specific alterations found in the blood indirectly diagnose the presence of MRD. Liquid biopsies thus have the potential to detect MRD, allowing, among other things, the detection of circulating tumor DNA (ctDNA), circulating tumor cells (CTC), or tumor-specific microRNA. Although liquid biopsy is increasingly studied, several technical issues still limit its clinical applicability: low sensitivity, poor standardization or reproducibility, and lack of randomized trials demonstrating its clinical benefit. Being able to detect MRD could give clinicians a more comprehensive view of the risk of relapse of their patients and could select patients requiring treatment escalation with the goal of improving cancer survival. In this review, we are discussing the different methodologies used and investigated to detect MRD in solid cancers, their respective potentials and issues, and the clinical impacts that MRD detection will have on the management of cancer patients

    Cinacalcet sustainedly prevents pancreatitis in a child with a compound heterozygous SPINK1/AP2S1 mutation

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    Familial hypocalciuric hypercalcemia is an autosomal dominant genetic disorder characterized by hypercalcemia associated with inappropriate hypocalciuria and normal parathyroid hormone levels. Acute recurrent pancreatitis (ARP) is rare in children. Predisposing factors include hypercalcemia and mutations in the serine protease inhibitor Kazal-type 1 (SPINK1) gene. The disease carries a heavy morbidity and preventive treatment options are scant. Here, we report a child with a novel genetic/metabolic form of ARP associated with compound heterozygous SPINK1/AP2S1 (adaptor protein-2 σ1-subunit) mutations, recurrence of which was completely abrogated for 6 years by cinacalcet treatment

    Atypical phenotype? The answer’s in the genotype: AGS caused by a novel RNASEH2C variant combined with XLA caused by a BTK deficiency.

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    Atypical phenotype? The answer’s in the genotype: AGS caused by a novel RNASEH2C variant combined with XLA caused by a BTK deficiency
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