@article{LiedtkeHofmannJakobetal.2020, author = {Liedtke, Daniel and Hofmann, Christine and Jakob, Franz and Klopocki, Eva and Graser, Stephanie}, title = {Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease}, series = {Biomolecules}, volume = {10}, journal = {Biomolecules}, number = {12}, publisher = {MDPI}, issn = {2218-273X}, doi = {10.3390/biom10121648}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220096}, year = {2020}, abstract = {Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme's role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.}, language = {en} } @article{KolokotronisPlutaKlopockietal.2020, author = {Kolokotronis, Konstantinos and Pluta, Natalie and Klopocki, Eva and Kunstmann, Erdmute and Messroghli, Daniel and Maack, Christoph and Tejman-Yarden, Shai and Arad, Michael and Rost, Simone and Gerull, Brenda}, title = {New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis}, series = {Journal of Clinical Medicine}, volume = {9}, journal = {Journal of Clinical Medicine}, number = {7}, doi = {10.3390/jcm9072168}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236094}, year = {2020}, abstract = {Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64\% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69\%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13\% and 5\%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype-genotype correlations, as well as the identification of novel candidate genes.}, language = {en} } @article{ManukjanWiegeringReindletal.2020, author = {Manukjan, Georgi and Wiegering, Verena and Reindl, Tobias and Strauß, Gabriele and Klopocki, Eva and Schulze, Harald and Andres, Oliver}, title = {Novel variants in FERMT3 and RASGRP2 - Genetic linkage in Glanzmann-like bleeding disorders}, series = {Pediatric Blood \& Cancer}, volume = {67}, journal = {Pediatric Blood \& Cancer}, number = {2}, doi = {10.1002/pbc.28078}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208129}, pages = {e28078}, year = {2020}, abstract = {Defects of platelet intracellular signaling can result in severe platelet dysfunction. Several mutations in each of the linked genes FERMT3 and RASGRP2 on chromosome 11 causing a Glanzmann-like bleeding phenotype have been identified so far. We report on novel variants in two unrelated pediatric patients with severe bleeding diathesis—one with leukocyte adhesion deficiency type III due to a homozygous frameshift in FERMT3 and the other with homozygous variants in both, FERMT3 and RASGRP2 . We focus on the challenging genetic and functional variant assessment and aim to accentuate the risk of obtaining misleading results due to the phenomenon of genetic linkage.}, language = {en} } @article{OhlebuschBorstFrankenbachetal.2020, author = {Ohlebusch, Barbara and Borst, Angela and Frankenbach, Tina and Klopocki, Eva and Jakob, Franz and Liedtke, Daniel and Graser, Stephanie}, title = {Investigation of alpl expression and Tnap-activity in zebrafish implies conserved functions during skeletal and neuronal development}, series = {Scientific Reports}, volume = {10}, journal = {Scientific Reports}, doi = {10.1038/s41598-020-70152-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230024}, year = {2020}, abstract = {Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissue-nonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish (Danio rerio) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. Additionally, we determined functional consequences of Tnap inhibition on neural and skeletal development in zebrafish. We show that expression of alpl is present during embryonic stages and in adult neuronal tissues. Analyses of enzyme function reveal zones of pronounced Tnap-activity within the telencephalon and the mesencephalon. Treatment of zebrafish embryos with chemical Tnap inhibitors followed by axonal and cartilage/mineralized tissue staining imply functional consequences of Tnap deficiency on neuronal and skeletal development. Based on the results from neuronal and skeletal tissue analyses, which demonstrate an evolutionary conserved role of this enzyme, we consider zebrafish as a promising species for modeling HPP in order to discover new potential therapy strategies in the long-term.}, language = {en} }