Browsing by Person "Ott, Tim"

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Identification of novel genes including NAV2 associated with isolated tall stature
(2023) Weiss, Birgit; Ott, Tim; Vick, Philipp; Lui, Julian C.; Roeth, Ralph; Vogel, Sebastian; Waldmüller, Stephan; Hoffmann, Sandra; Baron, Jeffrey; Wit, Jan M.; Rappold, Gudrun A.
Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with normal stature by whole exome sequencing; the tallest man had a height of 211 cm. Six heterozygous gene variants predicted as damaging were shared among the four genetically related tall individuals and not present in a family member with normal height. To gain insight into the putative role of these candidate genes in bone growth, we assessed the transcriptome of murine growth plate by microarray and RNA Seq. Two (Ift140, Nav2) of the six genes were well-expressed in the growth plate. Nav2 (p-value 1.91E-62) as well as Ift140 (p-value of 2.98E-06) showed significant downregulation of gene expression between the proliferative and hypertrophic zone, suggesting that these genes may be involved in the regulation of chondrocyte proliferation and/or hypertrophic differentiation. IFT140, NAV2 and SCAF11 have also significantly associated with height in GWAS studies. Pathway and network analysis indicated functional connections between IFT140, NAV2 and SCAF11 and previously associated (tall) stature genes. Knockout of the all-trans retinoic acid responsive gene, neuron navigator 2 NAV2, in Xenopus supports its functional role as a growth promotor. Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype.
MMP21 behaves as a fluid flow transported morphogen to impart laterality during development
(2025) Ott, Tim; Brugger, Amelie; Szenker-Ravi, Emmanuelle; Kurrle, Yvonne; Aberle, Olivia; Tisler, Matthias; Blum, Martin; Whalen, Sandra; Bouvagnet, Patrice; Reversade, Bruno; Schweickert, Axel
Heterotaxy (HTX) is frequently caused by deleterious variants in the gene encoding Matrix metallopeptidase 21 (MMP21). However, the underlying pathomechanism has not been ascertained. In this study, we report on a novel HTX-associated MMP21 knockout allele in humans and investigate the peptidase’s role during laterality development using Xenopus embryos as animal model. The targeted inactivation of mmp21 in f0 mutant Xenopus successfully phenocopied the human HTX condition, yet the cilia-driven leftward fluid flow, which initiates asymmetric gene activity at the left-right organizer (LRO), was unaltered in mmp21 null frogs. Instead, our analysis of downstream events revealed that flow response, the left-sided repression of dand5, could not take place. Remarkably, gain-of-function experiments demonstrated that Mmp21 spreads over LRO cells and triggers flow response. Additionally, Mmp21 functions upstream of Cirop, another metallopeptidase, which we found specifically localized to LRO cilia. Thus, our findings suggest that Mmp21 may be the long-sought morphogen, which is actively transported by the leftward fluid flow to Cirop-laden cilia, in order to specify the left side of the embryo.
Studies of human genetic diseases and developmental processes with the frog Xenopus laevis
(2020) Ott, Tim; Blum, Martin
Next generation sequencing is a driving force behind the identification of genes and alleles that are suspected to cause human genetic diseases. In silico tools are routinely used in the clinical everyday life to characterize unknown genotypes. However, these tools have a limited predictive accuracy and can only provide a first-line assessment. Especially un- or less studied genes require in every case predictive in vivo model systems that allow conclusions about disease associations. Classically, mice and zebrafish are utilized for such research, which concomitantly deepens the understanding of the involved developmental processes. In this collection of studies, the African clawed frog Xenopus laevis was used to explore and promote its suitability for the analysis of potential human disease genes, variants and their associated developmental processes. The first chapters covers potential candidate genes for primary ciliary dyskinesia (PCD). The second chapter addresses if an actin based motor protein and a novel metzincin peptidase, encoded by myosin ID (MYO1D) and leishmanolysin like peptidase (LMLN2)/tout-de-travers (TDT), respectively, are potentially causative for PCD independent laterality defects. The third chapter deals with two candidates for neurodevelopmental disorders, namely hyaluronan mediated motility receptor (HMMR) and progesterone immunomodulatory binding factor 1 (PIBF1).