73 research outputs found
The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF binding sites
No full textAt chromosome 11p15.5, the imprinting centre 1 (IC1) controls the parent of origin-specific expression of the IGF2 and H19 genes. The 5 kb IC1 region contains multiple target sites (CTS) for the zinc-finger protein CTCF, whose binding on the maternal chromosome prevents the activation of IGF2 and allows that of H19 by common enhancers. CTCF binding helps maintaining the maternal IC1 methylation-free, whereas on the paternal chromosome gamete-inherited DNA methylation inhibits CTCF interaction and enhancer-blocking activity resulting in IGF2 activation and H19 silencing. Maternally inherited 1.4-2.2 kb deletions are associated with methylation of the residual CTSs and Beckwith-Wiedemann syndrome, although with different penetrance and expressivity. We explored the relationship between IC1 microdeletions and phenotype by analysing a number of previously described and novel mutant alleles. We used a highly quantitative assay based on next generation sequencing to measure DNA methylation in affected families and analysed enhancer-blocking activity and CTCF binding in cultured cells. We demonstrate that the microdeletions mostly affect IC1 function and CTCF binding by changing CTS spacing. Thus, the extent of IC1 inactivation and the clinical phenotype are influenced by the arrangement of the residual CTSs. A CTS spacing similar to the wild-type allele results in moderate IC1 inactivation and is associated with stochastic DNA methylation of the maternal IC1 and incomplete penetrance. Microdeletions with different CTS spacing display severe IC1 inactivation and are associated with IC1 hypermethylation and complete penetrance. Careful characterization of the IC1 microdeletions is therefore needed to predict recurrence risks and phenotypical outcomes. © The Author 2012. Published by Oxford University Press
Professional Skepticism: Practitioners’ Perceptions And Training Practices
No full textWhile regulators criticize auditors for lacking appropriate professional skepticism (SEC, 2010, 2013; PCAOB, 2012), auditing standards lack a clear, consistent definition (Nelson, 2009; Hurtt, Brown-Liburd, Earley, & Krishnamoorthy, 2013), leaving application of professional skepticism “open to interpretation” (Glover & Prawitt, 2013, p. 2). If individual auditors view professional skepticism as open to interpretation (i.e., subjective), auditors may believe they are appropriately applying standards on professional skepticism based on their individual interpretations. However, if regulators apply a different definition of professional skepticism when reviewing auditors’ work, this may help explain ongoing criticisms from regulators stating auditors lack appropriate professional skepticism. The author reports insights of 66 auditors’ perceptions and finds the majority believe professional skepticism has a subjective (as opposed to uniform) definition. This finding is consistent across auditor rank and firm size, suggesting the potential for variations in application of professional skepticism in practice. Supplemental analyses indicate tax practitioners are more likely than auditors to view professional skepticism as subjective, particularly at the partner rank. The author presents professional skepticism training practices for 25 firms that suggest most firms recognize the importance of professional skepticism training and its regular reinforcement. However, there are concerns surrounding the fact that mentoring is listed as the most common training method, which lacks benefits of more formal training activities. Overall, this study provides relevant insights from practitioners and strengthens recent calls for developing a “common definition and shared understanding” of professional skepticism and a framework for evaluating application of professional skepticism (Glover & Prawitt, 2014, p. 5-6)
Genetic testing in inherited endocrine disorders: Joint position paper of the European reference network on rare endocrine conditions (Endo-ERN)
No full textBackground: With the development of molecular high-throughput assays (i.e. next generation sequencing), the knowledge on the contribution of genetic and epigenetic alterations to the etiology of inherited endocrine disorders has massively expanded. However, the rapid implementation of these new molecular tools in the diagnostic settings makes the interpretation of diagnostic data increasingly complex. Main body: This joint paper of the ENDO-ERN members aims to overview chances, challenges, limitations and relevance of comprehensive genetic diagnostic testing in rare endocrine conditions in order to achieve an early molecular diagnosis. This early diagnosis of a genetically based endocrine disorder contributes to a precise management and helps the patients and their families in their self-determined planning of life. Furthermore, the identification of a causative (epi)genetic alteration allows an accurate prognosis of recurrence risks for family planning as the basis of genetic counselling. Asymptomatic carriers of pathogenic variants can be identified, and prenatal testing might be offered, where appropriate. Conclusions: The decision on genetic testing in the diagnostic workup of endocrine disorders should be based on their appropriateness to reliably detect the disease-causing and -modifying mutation, their informational value, and cost-effectiveness. The future assessment of data from different omic approaches should be embedded in interdisciplinary discussions using all available clinical and molecular data
Beckwith-Wiedemann-Syndrom
No full textZusammenfassung
Das Beckwith-Wiedemann-Syndrom (BWS) ist ein pädiatrisches Überwuchssyndrom mit variablem klinischem Erscheinungsbild. Obwohl die betroffenen Kinder mit zunehmendem Alter immer normaler aussehen, ist es wichtig, die Diagnose BWS zu stellen. Gründe sind mögliche syndromspezifische Komplikationen, insbesondere ein 400-fach erhöhtes Risiko der Patienten, an bestimmten embryonalen Tumoren – Nephroblastome (Wilms-Tumoren), Hepatoblastome u. a. – innerhalb der ersten Lebensjahre zu erkranken. Klinisch überlappt das BWS mit anderen Krankheitsentitäten, sodass eine eindeutige molekulargenetische Diagnostik zur Risikoabschätzung und adäquaten Therapie wünschenswert ist. Molekular ist das BWS mit der Chromosomenregion 11p15.5 assoziiert, einer Region in der es 2 Cluster von Genen gibt, die dem genomischen Imprinting unterliegen. Bei den Patienten lassen sich Sequenzabweichungen in bestimmten Genen finden, die Mehrzahl weisen aber DNA-Methylierungsveränderungen auf, welche die Gendosis der funktionell zur Verfügung stehenden, monoallelisch aktiven 11p15.5-Gene pathogen beeinflussen. Zurzeit existiert nur eine sehr unvollständige Genotyp-Phänotyp-Korrelation. Aktuelle Forschungsarbeiten liefern Ansätze, die Ätiopathogenese des Syndroms molekular besser zu verstehen. So werden beispielsweise Interaktionspartner identifiziert, die das Imprinting der 11p15.5-Gene modifizieren und epigenetisch regulieren.</jats:p
Hypotherme Oxygenierung der Rattenleber reguliert Heat shock Protein Expression sowie Apoptose Induktion
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