A5106508525- DNA Repair Mechanisms
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Cancer-related Molecular Pathways
- Advanced biosensing and bioanalysis techniques
- RNA Research and Splicing
- Genetic factors in colorectal cancer
- Single-cell and spatial transcriptomics
- Cardiomyopathy and Myosin Studies
- Galectins and Cancer Biology
- Genetics and Neurodevelopmental Disorders
- RNA regulation and disease
- Genomics and Chromatin Dynamics
- Cytomegalovirus and herpesvirus research
- Protein Tyrosine Phosphatases
- Neurogenetic and Muscular Disorders Research
- Microtubule and mitosis dynamics
- Genomic variations and chromosomal abnormalities
- Data Quality and Management
- Peptidase Inhibition and Analysis
- Moyamoya disease diagnosis and treatment
- Ion Transport and Channel Regulation
- RNA Interference and Gene Delivery
- Cancer therapeutics and mechanisms
German Centre for Cardiovascular Research
2020-2025
Universitätsmedizin Göttingen
2018-2025
University of Cologne
2019
Czech Academy of Sciences, Institute of Molecular Genetics
2019
University of Sussex
2019
University of Birmingham
2019
All India Institute of Medical Sciences
2019
University of Göttingen
2018
Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
2015
Abstract Cardiomyocytes can be implanted to remuscularize the failing heart 1–7 . Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated hypothesis that epicardial engineered muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes stromal cells structurally functionally chronically limiting effects in rhesus macaques. After confirmation of...
Three pregnancies with male offspring in one family were complicated by severe polyhydramnios and prematurity. One fetus died; the other two had transient massive salt-wasting polyuria reminiscent of antenatal Bartter’s syndrome.
Background: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, delay, intellectual disability well cardiac hypertrophy. The underlying mechanism gain-of-function of the RAS–mitogen-activated protein kinase signaling pathway. However, our understanding pathophysiological alterations and mechanisms, especially associated cardiomyopathy, remains limited effective therapeutic...
Abstract Single cell multi-omics analysis has the potential to yield a comprehensive understanding of cellular events that underlie basis human diseases. The cardinal feature access this information is technology used for single-cell isolation, barcoding, and sequencing. Most currently RNA-sequencing platforms have limitations in several areas including selection, documentation library chemistry. In study, we describe novel high-throughput, full-length, approach combines CellenONE isolation...
DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway repair DSBs in mammalian cells, and mutations different NHEJ components have been described microcephalic syndromes associated, e.g. with short stature, facial dysmorphism immune dysfunction. By using...
Abstract Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one its least studied members. We discovered a de novo missense mutation patient clinically presenting rare Hallermann-Streiff syndrome (HSS). used genome editing to generate isogenic iPSC lines and model HSS relevant cell types. By combining genomics functional vivo vitro assays, we show that binds cohort autophagy stress response genes...
DNA double-strand breaks (DSBs) are highly toxic lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair DSB by, for example, activating pathways leading homologous recombination nonhomologous end joining. Additionally, MRN also plays an important role maintenance telomeres act as a stabilizer at replication forks. Mutations NBN MRE11 associated with Nijmegen breakage...
Dilated cardiomyopathy (DCM) belongs to the most frequent forms of mainly characterized by cardiac dilatation and reduced systolic function. Although cases DCM are classified as sporadic, 20-30% show a heritable pattern. Familial genetically heterogeneous, mutations in several genes have been identified that commonly play role cytoskeleton sarcomere-associated processes. Still, large number familial remain unsolved. Here, we report five individuals from three independent families who...
Abstract The non-homologous end joining (NHEJ) pathway is essential to repair DNA double-strand breaks. XRCC4 acts as a stabilizer of the ligase LIG4 in NHEJ process. In humans, pathogenic variants are responsible for microcephalic primordial dwarfism syndrome (MPD). Currently, 17 patients have been reported with -related MPD and we report 7 new from 6 different families, including one fetus. present short stature, severe microcephaly, neurodevelopmental disorder additional features, such...
Biallelic loss-of-function (LoF) variants in the BTRR complex members BLM , TOP3A RMI1 and RMI2 cause Bloom syndrome (BS). The mainly acts on DNA replication repair processes, dysfunction of this underlies, e.g., increased genomic instability cancer predisposition associated with BS phenotype. Here, we report CRISPR/Cas9-based genome-edited isogenic induced pluripotent stem cell (iPSC) models compound heterozygous LoF . cellular phenotype all three knockout (KO) iPSC lines included...
To address the relationship between novel mutations in polynucleotide 5'-kinase 3'-phosphatase (PNKP), DNA strand break repair, and neurologic disease.We have employed whole-exome sequencing, Sanger molecular/cellular biology.We describe here a patient with microcephaly early onset seizures (MCSZ) from Indian sub-continent harboring 2 PNKP, including pathogenic mutation fork-head associated domain. In addition, we confirm that MCSZ is hyperactivation of single-strand sensor protein poly...
Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated autosomal dominant and recessive human disorders. Autosomal variants tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy Charcot-Marie-Tooth disease, but recessively inherited phenotype yet be clearly defined. Seryl-tRNA (SARS1) has rarely an developmental disorder. Here, we report...
Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the molecular findings eight patients from six families diagnosed BS. We identified causative pathogenic variants in all including three different BLM one variant RMI1. The homozygous c.581_582delTT;p.Phe194* c.3164G>C;p.Cys1055Ser have already been reported BS patients, while...
STAG2 is a component of the large, evolutionarily highly conserved cohesin complex, which has been linked to various cellular processes like genome organization, DNA replication, gene expression, heterochromatin formation, sister chromatid cohesion, and repair. A wide spectrum germline variants in genes encoding subunits or regulators complex have previously identified cause distinct but phenotypically overlapping multisystem developmental disorders belonging group cohesinopathies....
The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. Within this family, FGFR2 is key regulator in many biological processes, e.g., cell proliferation, tumorigenesis, metastasis, and angiogenesis. Heterozygous activating non-mosaic germline variants have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses skeletal dysplasia syndromes. We report on girl with cutaneous nevi,...
Arthrogryposis multiplex congenita forms a broad group of clinically and etiologically heterogeneous disorders characterized by congenital joint contractures that involve at least two different parts the body. Neurological muscular are commonly underlying arthrogryposis. Here, we report five affected individuals from three independent families sharing an overlapping phenotype with affecting shoulder, elbow, hand, hip, knee foot as well scoliosis, reduced palmar plantar skin folds,...
Abstract The role of RNF43 as a cause an inherited predisposition to colorectal cancer (CRC) is yet be fully explored. This report presents our findings two individuals with CRC from single family carrying likely‐pathogenic germline variant in . proband (III:1) and the proband's mother (II:2) were diagnosed mismatch repair proficient CRCs at age 50 years 65 years, respectively. Both patients had BRAF V600E mutated colon tumours, indicating that arose sessile serrated lesions....
Abstract Variants in transcription factor p63 have been linked to several autosomal dominantly inherited malformation syndromes. These disorders show overlapping phenotypic characteristics with various combinations of the following features: ectodermal dysplasia, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypoplastic breasts and/or nipples, ankyloblepharon filiforme adnatum, hypospadias and cleft lip/palate. We describe a family six individuals presenting striking...
Bloom syndrome (BS) is an autosomal recessive disease clinically characterized by primary microcephaly, growth deficiency, immunodeficiency and predisposition to cancer. It mainly caused biallelic loss-of-function mutations in the BLM gene, which encodes helicase, acting DNA replication repair processes. Here, we describe gene expression profiles of three BS fibroblast cell lines harboring causative, truncating obtained single-cell (sc) transcriptome analysis. We compared scRNA transcription...
Abstract Mild clinical phenotypes of ataxia‐telangiectasia (variant A‐T) are associated with biallelic ATM variants resulting in residual function the kinase. At least one regulatory, missense, or leaky splice site mutation expression low level kinase activity was identified subjects variant A‐T. Studies on pathogenicity germline splicing c.1066‐6T>G have provided conflicting results. Using whole‐exome sequencing, we two variants, c.1066‐6T>G; [p.?], and c.2250G>A,...
Abstract Protein translation is an essential cellular process and dysfunctional protein causes various neurodevelopmental disorders. The eukaryotic elongation factor 1A (eEF1A) delivers aminoacyl‐tRNA to the ribosome, while eEF1B complex acts as a guanine exchange (GEF) of GTP for GDP indirectly catalyzing release eEF1A from ribosome. gene EEF1D encodes eEF1Bδ subunit complex. alternatively spliced giving rise one long three short isoforms. Two different homozygous, truncating variants in...
ABSTRACT Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies, with CHD6 being one its least studied members. Here, we discovered a de novo missense mutation patient clinically presenting rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS relevant cell types. show that binds cohort autophagy stress response genes across The HSS-mutation affects...
Background: Mild clinical phenotypes of Ataxia telangiectasia (variant A-T) are associated with biallelic ATM variants resulting in residual function the kinase. At least one regulatory, missense or leaky splice site mutation expression low level kinase activity was identified subjects variant A-T. Studies on pathogenicity germline splicing c.1066-6T>G have provided conflicting results.