The Valovka Laboratory: Molecular Basis of Rare Genetic Disorders
Our research deals with the clarification of molecular mechanisms implicated in rare, inherited diseases. Rare diseases are usually caused by genetic mutations in a broad spectrum of genes, ranging from metabolic enzymes to those that regulate immune function or those that cause cancer, which can affect almost any organ system in humans. As a part of the cooperation with the Department of Paediatrics I at MUI (Andreas Janecke and Thomas Müller) and the Department of Paediatrics and Adolescent Medicine at MUV (Julia Vodopiutz) in recent years, we have identified and studied several novel, pathogenic mutations in various genes, including PCNT, ACTB and DOCK7 (Waich et al., Clinical Genetics 2020; Baumann et al., Hum Mutat 2020; Haberlandt et al., Mol Genet Genomic Med 2021).
Novel PCNT Variants with an Unusual Clinical Presentation of MOPDII
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is a rare autosomal recessive disorder, characterised by extreme pre and postnatal growth restriction, skeletal dysplasia, dental anomalies and craniofacial dysmorphism, and often mild mental retardation. Biallelic loss‐of‐function mutations in the pericentrin gene (PCNT) have been defined as the cause of the disease. Here, we described a new case of MOPDII with an unusual, attenuated growth restriction and pachygyria. Compound heterozygosity for novel truncated PCNT variants was identified in a family with two affected siblings. Our studies revealed the expression of both mutated PCNT variants and showed their ability to partially retain the centrosome-associated functions in patient fibroblasts (Fig. 5). These findings explain the mild manifestation of MOPDII described and expand our knowledge of the clinical and molecular spectrum of this disease.
Novel Methodological Approach to Inhibitory Screening
Screening for synthetic and natural anti-inflammatory compounds forms another aspect of our research. In a collaboration with the Austrian Drug Screening Institute (ADSI), we established a screening platform to identify and characterise anti-inflammatory bioactive compounds in natural extracts. In the context of this work, we developed a high-throughput, fluorescent thermal shift-based method of detecting nuclear factor kappa B (NF-κB) binding to double stranded DNA (Leitner et al., Sci Rep 2021). This method allows the measurement of dose-dependent inhibitory effects on NF-κB DNA binding as well as accurate calculation of equilibrium binding constants.
Novel PCNT variants in MOPDII with attenuated growth restriction and pachygyria. Waich S, Janecke AR, Parson W, Greber-Platzer S, Müller T, Huber LA, Valovka T, Vodopiutz J. Clin Genet. 2020 Sep;98(3):282-287. doi: 10.1111/cge.13797. Epub 2020 Jul 7. PMID: 32557621
Characteristic facial features and cortical blindness distinguish the DOCK7-related epileptic encephalopathy. Haberlandt E, Valovka T, Janjic T, Müller T, Blatsios G, Karall D, Janecke AR. Mol Genet Genomic Med. 2021 Jan 20:e1607. doi: 10.1002/mgg3.1607. Online ahead of print. PMID: 33471954
Fluorescent thermal shift-based method for detection of NF-κB binding to double-stranded DNA. Leitner PD, Vietor I, Huber LA, Valovka T. Sci Rep. 2021 Jan 27;11(1):2331. doi: 10.1038/s41598-021-81743-1.PMID: 33504856
Julia Vodopiutz, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna
The Austrian Drug Screening Institute (ADSI)
Priv.-Doz. DDr. Taras Valovka
Phone: 0043 512 9003 70174