Limb-girdle muscular dystrophy 2D (LGMD2D) is an inherited myogenic disorder belonging to the group of muscular dystrophies. <em>Sgca-null</em> mouse is a knock-out model of LGMD2D. Little is known about cardiac phenotype characterization in this model at different ages. We conducted a prospective study to characterize cardiac <em>sgca-null</em> mice phenotype using high resolution Doppler echocardiography at different ages. Conventional echocardiography was performed on anesthetised mice using a Vevo 770 (Visualsonics) with 30 MHz cardiac probe. Wild Type (WT) and <em>sgca-null</em> mice were scanned at 13, 15 and 17 months. From M-mode, we measured interventricular septal (IVS) wall thickness, posterior wall (PW) thickness, and end-left ventricular diameter in systolic and diastolic. From the above parameters, we calculated left ventricular (LV) shortening fraction (SF), LV ejection fraction (EF) and LV mass. At age 13 months, PW diastolic thickness was increased in <em>sgca-null </em>mice (0.89±0.14 mm <em>vs</em> 0.73±0.2 mm; P=0.020) and LV mass was higher in <em>sgca-nul</em>l mice (LV mass 205.2 mg <em>vs</em> 143 mg; P=0.001). We found also dilation of the LV (LVEDD: 4.84 mm <em>vs</em> 4.29 mm; P=0.019) in <em>sgca-null</em> mice. At age 15 months, dilation of the LV (LVEDD: 4.86 mm <em>vs</em> 4 mm; P=0.05) with an increase of the LV mass (165.7 mg <em>vs</em> 127.12; P=0.03) are found in <em>sgca-null</em> mice. At age 17 months, we found a decrease of the PW thickening (17% <em>vs</em> 30%; P=0.036). This work provides echocardiographic insights for the assessment of pharmaceutical therapies in <em>sgca-null</em> mice.
Background The effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF. Methods Genetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases). Results Lower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74–0.93, P = 0.001) and 0.95 (95% CI 0.93–0.97, P = 8 × 10 −6 ). Conversely, lower α2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05–1.12, P = 3 × 10 −7 ). No evidence of an effect of lower ß2 activity on HF risk was found: OR 0.99 (95% CI 0.92–1.07, P = 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease. Conclusions This study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.
Journal Article Mapping of the formin gene and exclusion as a candidate gene for the autosomal recessive form of limb-girdle muscular dystrophy Get access Isabelle Richard, Isabelle Richard Search for other works by this author on: Oxford Academic PubMed Google Scholar Odile Broux, Odile Broux Search for other works by this author on: Oxford Academic PubMed Google Scholar Dominique Hillaire, Dominique Hillaire Search for other works by this author on: Oxford Academic PubMed Google Scholar Dorra Cherif, Dorra Cherif 1Unité de Recherches INSERMU 301, 27 Rue Juliette Dodu, 75010, Paris2Centre d'Etude du Polymorphisme Humain27 Rue Juliette Dodu, 75010, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Françoise Fougerousse, Françoise Fougerousse Search for other works by this author on: Oxford Academic PubMed Google Scholar Daniel Cohen, Daniel Cohen 2Centre d'Etude du Polymorphisme Humain27 Rue Juliette Dodu, 75010, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Jacques S. Beckmann Jacques S. Beckmann * 2Centre d'Etude du Polymorphisme Humain27 Rue Juliette Dodu, 75010, Paris, France * To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Molecular Genetics, Volume 1, Issue 8, October 1992, Pages 621–624, https://doi.org/10.1093/hmg/1.8.621 Published: 01 October 1992 Article history Received: 14 July 1992 Revision received: 10 September 1992 Accepted: 10 September 1992 Published: 01 October 1992
Calpain 3 is a nonlysosomal cysteine protease whose biological functions remain unknown. We previously demonstrated that this protease is altered in limb girdle muscular dystrophy type 2A patients. Preliminary observations suggested that its gene is subjected to alternative splicing. In this paper, we characterize transcriptional and posttranscriptional events leading to alterations involving the NS, IS1, and IS2 regions and/or the calcium binding domains of the mouse calpain 3 gene (capn3). These events can be divided into three groups: (i) splicing of exons that preserve the translation frame, (ii) inclusion of two distinct intronic sequences between exons 16 and 17 that disrupt the frame and would lead, if translated, to a truncated protein lacking domain IV, and (iii) use of an alternative first exon specific to lens tissue. In addition, expression of these isoforms seems to be regulated. Investigation of the proteolytic activities and titin binding abilities of the translation products of some of these isoforms clearly indicated that removal of these different protein segments affects differentially the biochemical properties examined. In particular, removal of exon 6 impaired the autolytic but not fodrinolytic activity and loss of exon 16 led to an increased titin binding and a loss of fodrinolytic activity. These results are likely to impact our understanding of the pathophysiology of calpainopathies and the development of therapeutic strategies.
Journal Article Trinucleotide repeat polymorphism at the human insulin-like growth factor I receptor gene (IGF1R) Get access R. Meloni, R. Meloni Centre d'Etude du Polymorphisme Humain27 rue Juliette Dodu, 75010 Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar F. Fougerousse, F. Fougerousse Centre d'Etude du Polymorphisme Humain27 rue Juliette Dodu, 75010 Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar C. Roudaut, C. Roudaut Centre d'Etude du Polymorphisme Humain27 rue Juliette Dodu, 75010 Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar J.S. Beckmann J.S. Beckmann Centre d'Etude du Polymorphisme Humain27 rue Juliette Dodu, 75010 Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 20, Issue 6, 25 March 1992, Page 1427, https://doi.org/10.1093/nar/20.6.1427 Published: 25 March 1992
Our understanding of early human development has been impeded by the general difficulty in obtaining suitable samples for study. As a result, and because of the extraordinarily high degree of evolutionary conservation of many developmentally important genes and developmental pathways, great reliance has been placed on extrapolation from animal models of development, principally the mouse. However, the strong evolutionary conservation of coding sequence for developmentally important genes does not necessarily mean that their expression patterns are as highly conserved. The very recent availability of human embryonic samples for gene expression studies has now permitted for the first time an assessment of the degree to which we can confidently extrapolate from studies of rodent gene expression patterns. We have found significant human-mouse differences in embryonic expression patterns for a variety of genes. We present detailed data for two illustrative examples. Wnt7a, a very highly conserved gene known to be important in early development, shows significant differences in spatial and temporal expression patterns in the developing brain (midbrain, telencephalon) of man and mice. CAPN3, the locus for LGMD2A limb girdle muscular dystrophy, and its mouse orthologue differ extensively in expression in embryonic heart, lens and smooth muscle. Our study also shows how molecular analyses, while providing explanations for the observed differences, can be important in providing insights into mammalian evolution.
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