TY  - JOUR
A1  - Doll, Julia
A1  - Kolb, Susanne
A1  - Schnapp, Linda
A1  - Rad, Aboulfazl
A1  - Rüschendorf, Franz
A1  - Khan, Imran
A1  - Adli, Abolfazl
A1  - Hasanzadeh, Atefeh
A1  - Liedtke, Daniel
A1  - Knaup, Sabine
A1  - Hofrichter, Michaela AH
A1  - Müller, Tobias
A1  - Dittrich, Marcus
A1  - Kong, Il-Keun
A1  - Kim, Hyung-Goo
A1  - Haaf, Thomas
A1  - Vona, Barbara
T1  - Novel loss-of-function variants in CDC14A are associated with recessive sensorineural hearing loss in Iranian and Pakistani patients
JF  - International Journal of Molecular Sciences
N2  - CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss.
KW  - CDC14A
KW  - DFNB32
KW  - autosomal recessive hearing loss
KW  - exome sequencing
KW  - splicing
KW  - frameshift
KW  - non-sense mediated mRNA decay
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285142
SN  - 1422-0067
VL  - 21
IS  - 1
ER  - 
TY  - JOUR
A1  - Liedtke, Daniel
A1  - Orth, Melanie
A1  - Meissler, Michelle
A1  - Geuer, Sinje
A1  - Knaup, Sabine
A1  - Köblitz, Isabell
A1  - Klopocki, Eva
T1  - ECM alterations in fndc3a (fibronectin domain containing protein 3A) deficient zebrafish cause temporal fin development and regeneration defects
JF  - Scientific Reports
N2  - Fin development and regeneration are complex biological processes that are highly relevant in teleost fish. They share genetic factors, signaling pathways and cellular properties to coordinate formation of regularly shaped extremities. Especially correct tissue structure defined by extracellular matrix (ECM) formation is essential. Gene expression and protein localization studies demonstrated expression of fndc3a (fibronectin domain containing protein 3a) in both developing and regenerating caudal fins of zebrafish (Danio rerio). We established a hypomorphic fndc3a mutant line (fndc3a\(^{wue1/wue1}\)) via CRISPR/Cas9, exhibiting phenotypic malformations and changed gene expression patterns during early stages of median fin fold development. These developmental effects are mostly temporary, but result in a fraction of adults with permanent tail fin deformations. In addition, caudal fin regeneration in adult fndc3a\(^{wue1/wue1}\) mutants is hampered by interference with actinotrichia formation and epidermal cell organization. Investigation of the ECM implies that loss of epidermal tissue structure is a common cause for both of the observed defects. Our results thereby provide a molecular link between these developmental processes and foreshadow Fndc3a as a novel temporal regulator of epidermal cell properties during extremity development and regeneration in zebrafish.
KW  - Extracellular matrix
KW  - Limb development
KW  - Self-renewal
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202141
VL  - 9
ER  - 
TY  - JOUR
A1  - Menescal, Luciana
A1  - Schmidt, Cornelia
A1  - Liedtke, Daniel
A1  - Schartl, Manfred
T1  - Liver hyperplasia after tamoxifen induction of Myc in a transgenic medaka model
N2  - Myc is a global transcriptional regulator and one of the most frequently overexpressed oncoproteins in human tumors. It is well established that activation of Myc leads to enhanced cell proliferation but can also lead to increased apoptosis. The use of animal models expressing deregulated levels of Myc has helped to both elucidate its function in normal cells and give insight into how Myc initiates and maintains tumorigenesis. Analyses of the medaka (Oryzias latipes) genome uncovered the unexpected presence of two Myc gene copies in this teleost species. Comparison of these Myc versions to other vertebrate species revealed that one gene, myc17, differs by the loss of some conserved regulatory protein motifs present in all other known Myc genes. To investigate how such differences might affect the basic biological functions of Myc, we generated a tamoxifeninducible in vivo model utilizing a natural, fish-specific Myc gene. Using this model we show that, when activated, Myc17 leads to increased proliferation and to apoptosis in a dose-dependent manner, similar to human Myc. We have also shown that long-term Myc17 activation triggers liver hyperplasia in adult fish, allowing this newly established transgenic medaka model to be used to study the transition from hyperplasia to liver cancer and to identify Myc-induced tumorigenesis modifiers.
KW  - Biologie
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75316
ER  -