Identification and characterization of a novel RPGR isoform in human retina

Retinitis pigmentosa (RP) constitutes a major cause of blindness and the Retinitis Pigmentosa GTPase Regulator (RPGR) gene accounts for up to 80% of all X-linked RP cases. A novel isoform of RPGR, expressed in the human retina, was identified and characterized. It truncates the Regulator of Chromosome Condensation 1 (RCC1) homologous protein domain (RCC1h) of RPGR and mediates the formation of isoform-specific complexes with the RPGR-interacting protein 1 (RPGRIP1). Immunohistochemistry localized the novel RPGR isoform predominantly to inner segments of cone photoreceptors, where it colocalizes with RPGRIP1 in the human retina. In a patient with a mild RP phenotype, we identified a nucleotide substitution in a splicing regulator, which leads to 3.5 times higher levels of the transcripts coding for the novel RPGR isoform. The nucleotide substitution affects regulated alternative splicing of the novel RPGR isoform and suggests a tight adjustment of splicing as a prerequisite for proper function of photoreceptors.

Identification of novel mutations in X-linked retinitis pigmentosa families and implications for diagnostic testing

PURPOSE: The goal of this study was to identify mutations in X-chromosomal genes associated with retinitis pigmentosa (RP) in patients from Germany, The Netherlands, Denmark, and Switzerland. METHODS: In addition to all coding exons of RP2, exons 1 through 15, 9a, ORF15, 15a and 15b of RPGR were screened for mutations. PCR products were amplified from genomic DNA extracted from blood samples and analyzed by direct sequencing. In one family with apparently dominant inheritance of RP, linkage analysis identified an interval on the X chromosome containing RPGR, and mutation screening revealed a pathogenic variant in this gene. Patients of this family were examined clinically and by X-inactivation studies. RESULTS: This study included 141 RP families with possible X-chromosomal inheritance. In total, we identified 46 families with pathogenic sequence alterations in RPGR and RP2, of which 17 mutations have not been described previously. Two of the novel mutations represent the most 3'-terminal pathogenic sequence variants in RPGR and RP2 reported to date. In exon ORF15 of RPGR, we found eight novel and 14 known mutations. All lead to a disruption of open reading frame. Of the families with suggested X-chromosomal inheritance, 35% showed mutations in ORF15. In addition, we found five novel mutations in other exons of RPGR and four in RP2. Deletions in ORF15 of RPGR were identified in three families in which female carriers showed variable manifestation of the phenotype. Furthermore, an ORF15 mutation was found in an RP patient who additionally carries a 6.4 kbp deletion downstream of the coding region of exon ORF15. We did not identify mutations in 39 sporadic male cases from Switzerland. CONCLUSIONS: RPGR mutations were confirmed to be the most frequent cause of RP in families with an X-chromosomal inheritance pattern. We propose a screening strategy to provide molecular diagnostics in these families.

1509 - Johannes Calvin - 2009. Sein Wirken in Kirche und Gesellschaft. Essays zum 500. Geburtstag

Welche bleibenden Impulse haben Johannes Calvin und der Calvinismus Kirche und Gesellschaft bis heute gegeben? Mit dieser Frage beschäftigen sich anlässlich des 500. Geburtstags des Genfer Reformators die Autorinnen und die Autoren der vorliegenden Beiträge anhand ausgewählter theologischer und wirkungsgeschichtlicher Themen. Gleichzeitig bieten sie eine grundlegende und allgemein verständliche Einführung in Calvins Leben und Theologie, in seine kontinuierliche Relevanz für kirchliche, gesellschaftliche und politische Fragen sowie in die Geschichte der Reformation in der Schweiz und weltweit. Sie blenden dabei auch die kritischen Anfragen an Calvin nicht aus. Der im Auftrag des Schweizerischen Evangelischen Kirchenbunds herausgegebene Sammelband ist eine wissenschaftlich fundierte, leserfreundliche Einführung, die Fragestellungen anregt, Perspektiven eröffnet und Austausch ermöglicht. Mit Beiträgen von Philip Benedict, James D. Bratt, Emidio Campi, Eva-Maria Faber, Eric Fuchs, Wulfert de Greef, Christopher L. Elwood, Ulrich H. J. Körtner, Christian Link, Christian Moser, Andrew Pettegree, Christoph Strohm, Mario Turchetti