263 Cardiac characterization of sgca-null mouse, a model of alpha-sarcoglycanopathy, by using echocardiography

Alpha-sarcoglycanopathy (LGMD2D) is an autosomal recessive inherited limb-girdle muscular dystrophy caused by mutations in the alpha-sarcoglycan gene, SGCA. Disruption of SGCA gene in mouse (Sgca-null mouse) shares many of clinical pictures observed in patients. Mice disclose progressive muscular dystrophy. We sought to characterize cardiac function in this disease in order to evaluate target therapy. After shaving, Sgca-null mice were anaesthetized with isoflurane before performing echocardiography. Echocardiography was performed with a Vevo 770 Visuals Sonics (30 MHz cardiac probe). Mice were analysed at 5, 13, and 17 months.Control and Sgca-null mice were similar regarding age and heart rate. At age 5 months, in Sgca-null mice, we found significant anatomical differences regarding the inter-ventricular septal (IVS) wall thickness and the posterior wall (PW) thickness, as compared to their control. The IVS diastolic thickness was significantly increased in Sgca-null mice (0.91mm+/–0.06 vs 0.73 mm+/–0.02; p=0.003). Furthermore, the PW diastolic thickness was also increased in Sgca-null mice compared to WT (0.81mm+/–0.07 vs 0.69 mm+/–0.03; p=0.03). Also, LV mass was significantly increased in Sgca-null mice (147mg+/–15 vs 117.6mg+/–5.3; p=0. 02). At age 13 months, LV mass was significantly higher in Sgca-null mice (LV mass 205.22 mg vs 143 mg; p =0.001).The PW thickness was significantly different in the 2 groups (0.89 mm in Sgca-null vs 0.73 mm; p=0,02). Moreover, Sgca-null mice at 13 months disclosed dilatation of the left ventricle (LVEDD: 4.84mm vs 4.29 mm; p= 0.019). Systolic function was conserved in the 2 groups at 13 months regarding SF and EF.At age 17 months, we noted a decreasing of the posterior wall thickening (17% vs 30%; p= 0.036) and an increasing of the LV mass/weight (5.6 vs 3.9; p=0,016). No significant differences were found regarding the other anatomic echocardiography parameters.This study is unique and provides data that will help researchers to evaluate the efficiency of pharmaceutical or gene cardiac therapies

The genomics of heart failure: design and rationale of the HERMES consortium

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.</p

The genomics of heart failure: design and rationale of the HERMES consortium

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P &lt; 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction

A homeobox gene, vax2, controls the patterning of the eye dorsoventral axis

We have identified a transcription factor specifically expressed in the developing vertebrate eye. We named this gene vax2 because of the high degree of sequence similarity to the recently described vax1. Both in the human and mouse genomes, vax2 is localized in the vicinity of the emx1 gene. This mapping assignment, together with the previously reported colocalization of Vax1 and Emx2 in mouse, indicates that the vax and the emx genes may be organized in clusters. vax2 has a remarkable expression domain confined to the ventral portion of the prospective neural retina in mouse, human, and Xenopus. The overexpression of either the frog Xvax2 or the human VAX2 in Xenopus embryos leads to an aberrant eye phenotype and, in particular, determines a ventralizing effect on the developing eye. The expression domain of the transcription factor Xpax2, normally confined to the ventral developing retina, extends to the dorsal region of the retina after overexpression of vax2. On the other hand, the expression of Xvent2, a molecular marker of the dorsal retina, is strongly reduced. Furthermore, vax2 overexpression induces a striking expansion of the optic stalk, a structure deriving from the ventralmost region of the eye vesicle. Altogether, these data indicate that vax2 plays a crucial role in eye development and, in particular, in the specification of the ventral optic vesicle