Combining gene mapping and phenotype assessment for fast mutation finding in non consanguineous autosomal recessive retinitis pigmentosa: mutation finding in non consanguineous families

International audienceAmong inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ~60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely TULP1 and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for 2 novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for 2 novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only 2 affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization

A novel locus (CORD12) for autosomal dominant cone-rod dystrophy on chromosome 2q24.2-2q33.1

<p>Abstract</p> <p>Background</p> <p>Rod-cone dystrophy, also known as retinitis pigmentosa (RP), and cone-rod dystrophy (CRD) are degenerative retinal dystrophies leading to blindness. To identify new genes responsible for these diseases, we have studied one large non consanguineous French family with autosomal dominant (ad) CRD.</p> <p>Methods</p> <p>Family members underwent detailed ophthalmological examination. Linkage analysis using microsatellite markers and a whole-genome SNP analysis with the use of Affymetrix 250 K SNP chips were performed. Five candidate genes within the candidate region were screened for mutations by direct sequencing.</p> <p>Results</p> <p>We first excluded the involvement of known adRP and adCRD genes in the family by genotyping and linkage analysis. Then, we undertook a whole-genome scan on 22 individuals in the family. The analysis revealed a 41.3-Mb locus on position 2q24.2-2q33.1. This locus was confirmed by linkage analysis with specific markers of this region. The maximum LOD score was 2.86 at θ = 0 for this locus. Five candidate genes, <it>CERKL</it>, <it>BBS5, KLHL23, NEUROD1</it>, and <it>SF3B1 </it>within this locus, were not mutated.</p> <p>Conclusion</p> <p>A novel locus for adCRD, named <it>CORD12</it>, has been mapped to chromosome 2q24.2-2q33.1 in a non consanguineous French family.</p

Functional and Molecular Effects of Arginine Butyrate and Prednisone on Muscle and Heart in the mdx Mouse Model of Duchenne Muscular Dystrophy

The number of promising therapeutic interventions for Duchenne Muscular Dystrophy (DMD) is increasing rapidly. One of the proposed strategies is to use drugs that are known to act by multiple different mechanisms including inducing of homologous fetal form of adult genes, for example utrophin in place of dystrophin.In this study, we have treated mdx mice with arginine butyrate, prednisone, or a combination of arginine butyrate and prednisone for 6 months, beginning at 3 months of age, and have comprehensively evaluated the functional, biochemical, histological, and molecular effects of the treatments in this DMD model. Arginine butyrate treatment improved grip strength and decreased fibrosis in the gastrocnemius muscle, but did not produce significant improvement in muscle and cardiac histology, heart function, behavioral measurements, or serum creatine kinase levels. In contrast, 6 months of chronic continuous prednisone treatment resulted in deterioration in functional, histological, and biochemical measures. Arginine butyrate-treated mice gene expression profiling experiments revealed that several genes that control cell proliferation, growth and differentiation are differentially expressed consistent with its histone deacetylase inhibitory activity when compared to control (saline-treated) mdx mice. Prednisone and combination treated groups showed alterations in the expression of genes that control fibrosis, inflammation, myogenesis and atrophy.These data indicate that 6 months treatment with arginine butyrate can produce modest beneficial effects on dystrophic pathology in mdx mice by reducing fibrosis and promoting muscle function while chronic continuous treatment with prednisone showed deleterious effects to skeletal and cardiac muscle. Our results clearly indicate the usefulness of multiple assays systems to monitor both beneficial and toxic effects of drugs with broad range of in vivo activity

Nouvelles approches en région Rhône-Alpes

Chazalette Andrée. Nouvelles approches en région Rhône-Alpes. In: Hommes et Migrations, n°1111, mars 1988. La formation… pour quels emplois ? pp. 26-36

The European Sovereign Debt Crisis

Judge Jean-Christophe Chazalette is an Appellate Justice of the Court of Appeal of Paris. Judge Chazalette holds an LL.M degree from Panthéon-Sorbonne University and a J.S.D. from the French National School for the Judiciary. He has served as Chief Justice of the Superior Court of Lisieux, Deputy Secretary General of the Court of Appeal of Paris, and Appellate Justice of the Court of Appeal of Versailles. Currently in the Court of Appeal of Paris, he is also Chair of the Ethics and Appointment Committee of the European Agency for Arbitration, Conciliation, Expertise and Mediation

Mucoviscidose de détection tardive (modalités d'approche diagnostique)

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

alpha7B integrin changes in mdx mouse muscles after L-arginine administration.

Muscle fibers attach to laminin in the basal lamina using two mechanisms, i.e., dystrophin with its associated proteins and alpha7beta1 integrin. In humans, gene-mutation defects in one member of these complexes result in muscular dystrophies. This study revealed changes after L-arginine treatment of utrophin-associated proteins and the alpha7B integrin subunit in mdx mouse, a dystrophin-deficient animal model. In the two studied muscles (cardiac muscle and diaphragm), the alpha7B integrin subunit was increased in 5-week-old treated mice. Interestingly, the diaphragm histopathological appearance was significantly improved by L-arginine administration. These results highlight a possible way to compensate for dystrophin deficiency via alpha7beta1 integrin