Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor

Rozmahel, Richard; Wilschanski, Michael; Matin, Angabin; Plyte, S.; Oliver, Mary G.; Auerbach, Wojtek; Moore, Aideen M.; Forstner, Janet F.; Durie, Peter R.; Nadeau, Joseph H.; Bear, Christine E.; Tsui, Lap Chee

doi:10.1038/ng0396-280

Cited by 365 publications

(254 citation statements)

References 29 publications

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“…Therefore, identification of the precise genes responsible for a genetic effect can be problematic. For example, genetic regions that modify cystic fibrosis have been identified in this same region of chromosome 7 in mice and the orthologous region of chromosome 19 in humans (36,37). This same genomic interval, as noted in this study, also includes the TGFB1 gene itself.…”

Section: Figuresupporting

confidence: 65%

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Heydemann¹,

Ceco²,

Lim³

et al. 2009

J. Clin. Invest.

183

240

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Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-β-binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-β-binding protein that sequesters TGF-β and regulates its availability for binding to the TGF-β receptor. Insertion of 12 amino acids into the proline-rich region of LTBP4 reduced proteolytic cleavage and was associated with reduced TGF-β signaling, decreased fibrosis, and improved muscle pathology in a mouse model of muscular dystrophy. In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-β signaling and modify outcomes in muscular dystrophy.

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Section: Figuresupporting

confidence: 65%

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Heydemann¹,

Ceco²,

Lim³

et al. 2009

J. Clin. Invest.

183

240

View full text Add to dashboard Cite

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“…Different explanations have been proposed for such a wide spectrum of clinical manifestations. 13 These considerations are, nevertheless, beyond the scope of our review.…”

Section: Cystic Fibrosismentioning

confidence: 86%

Cystic fibrosis, atopy, asthma and ABPA

Antunes

Fernandes

Borrego

et al. 2010

Allergologia et Immunopathologia

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The role of atopy on cystic fibrosis (CF) progression remains unclear but evidence suggests that it may influence the appearance of co-morbid conditions such as CF asthma or allergic bronchopulmonary aspergillosis (ABPA). Recognising asthma in patients with CF is not always easy but the identification of atopic markers favours the diagnosis. Physicians should be aware of this fact in order to achieve a better control of respiratory symptoms in patients with CF. Bronchial mucosa inflammation and abnormal mucus predispose to mould colonisation. These patients are at higher risk of allergic sensitisation, especially when atopic susceptibility is present. In the particular case of A. fumigatus, allergic sensitisation precedes ABPA development, which occurs in up to 10% of CF patients. Progression of lung function deterioration is most strikingly pronounced in patients with ABPA. Therefore, sensitisation with A. fumigatus should be regularly tested in patients with CF, especially those at higher risk. Recombinant allergens constitute an important advance in differentiating Aspergillus sensitisation from ABPA itself.

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“…A locus was identified on mouse chromosome 7 that modified intestinal disease in homozygous mutant mice (Rozmahel et al 1996) and subsequently a similar modifier was mapped to human chromosome 19, in the region syntenic to the mouse locus (Zielenski et al 1999). Unfortunately, the gene involved remains unknown.…”

Section: How Much Does Genetic Architecture Vary Between Phenotypes?mentioning

confidence: 99%

Genetic architecture of quantitative traits in mice, flies, and humans

Flint¹,

Mackay²

2009

Genome Res.

409

364

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We compare and contrast the genetic architecture of quantitative phenotypes in two genetically well-characterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, with that found in our own species from recent successes in genome-wide association studies. We show that the current model of large numbers of loci, each of small effect, is true for all species examined, and that discrepancies can be largely explained by differences in the experimental designs used. We argue that the distribution of effect size of common variants is the same for all phenotypes regardless of species, and we discuss the importance of epistasis, pleiotropy, and gene by environment interactions. Despite substantial advances in mapping quantitative trait loci, the identification of the quantitative trait genes and ultimately the sequence variants has proved more difficult, so that our information on the molecular basis of quantitative variation remains limited. Nevertheless, available data indicate that many variants lie outside genes, presumably in regulatory regions of the genome, where they act by altering gene expression. As yet there are very few instances where homologous quantitative trait loci, or quantitative trait genes, have been identified in multiple species, but the availability of high-resolution mapping data will soon make it possible to test the degree of overlap between species.Recent successes in mapping quantitative trait loci (QTLs) that contribute to phenotypic variation in humans and model organisms make it possible to address important questions about the genetic architecture of quantitative phenotypes, such as the likely number of loci, their mode of genetic action, and interaction with each other and with the environment. An understanding of the genetic architecture of quantitative traits is not only important in its own right, it will also inform studies that seek to proceed to the identification of the quantitative trait genes (QTGs) and the quantitative trait nucleotide (QTN) variants, the functional changes in DNA sequence that contribute to trait variation.In this work we use examples from two genetically wellcharacterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, to discuss how an understanding of the genetic architecture of quantitative phenotypes in model organisms informs mapping experiments in human genetics. In our discussion of the latter, we draw upon the recent successful application of genome-wide association studies (GWAS) to both quantitative phenotypes (such as height and weight) and disease phenotypes (assuming that the genetic architecture of common disease is similar, if not identical, to that of quantitative phenotypes).Genetic architecture has been the subject of a number of recent reviews, most of which deal with information from a single model organism (Mackay 2004) or review a small number of phenotypes (Kendler and Greenspan 2006). Here, our purpose is different. We tackle three relate...

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Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor

Cited by 365 publications

References 29 publications

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Cystic fibrosis, atopy, asthma and ABPA

Genetic architecture of quantitative traits in mice, flies, and humans

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