A5083716640- Protein Tyrosine Phosphatases
- Galectins and Cancer Biology
- Peptidase Inhibition and Analysis
- RNA modifications and cancer
- Lysosomal Storage Disorders Research
- PI3K/AKT/mTOR signaling in cancer
- Ubiquitin and proteasome pathways
- Genetics and Neurodevelopmental Disorders
- Childhood Cancer Survivors' Quality of Life
- Growth Hormone and Insulin-like Growth Factors
- Carbohydrate Chemistry and Synthesis
- Protein Kinase Regulation and GTPase Signaling
- Genetic and rare skin diseases.
- Hedgehog Signaling Pathway Studies
- Dermatological and Skeletal Disorders
- Cytokine Signaling Pathways and Interactions
- Eosinophilic Disorders and Syndromes
- Biochemical and Molecular Research
University Hospital Magdeburg
2012-2021
Otto-von-Guericke University Magdeburg
2014-2020
Washington Center
2015
University of Washington
2015
Somatic mutations affecting components of the Ras-MAPK pathway are a common feature cancer, whereas germline Ras cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These ‘RASopathies’ also represent cancer-prone syndromes, but quantitative cancer risks remain unknown. We investigated occurrence childhood benign malignant tumours central nervous system in group 735 individuals with signalling genes by matching their information German Childhood...
The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous caused by functional dysregulation signal transducers regulatory proteins with roles in RAS/extracellular signal-regulated kinase (ERK) transduction...
Oculoectodermal syndrome ( OES ) and encephalocraniocutaneous lipomatosis ECCL are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor‐like lesions, others. About 20 cases with more than 50 patients have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole‐genome sequencing has led the identification of somatic KRAS mutations, p. Leu19Phe...
Germline mutations in PTPN11, the gene encoding Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on identification of five different PTPN11 missense changes affecting residues Leu261 , Leu262 and Arg265 16 unrelated individuals with clinical diagnosis NS or features suggestive for this disorder, specifying novel disease-causing mutation cluster. Expression...
Noonan syndrome (NS) is a relatively common developmental disorder with pleomorphic phenotype. Mutations causing NS alter genes encoding proteins involved in the RAS-MAPK pathway. We and others identified Casitas B-lineage lymphoma proto-oncogene (CBL), which encodes an E3-ubiquitin ligase acting as tumor suppressor myeloid malignancies, disease gene underlying condition clinically related to NS. Here, we further explored spectrum of germline CBL mutations their associated mutation scanning...
The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among RASopathies, is characterized mainly short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS related phenotypes. We describe two unrelated patients presenting hypertrophic cardiomyopathy (HCM) dysmorphic features suggestive NS. One them died neonatal period because...
Costello syndrome is a congenital disorder comprising characteristic face, severe feeding difficulties, skeletal, cardiac and skin abnormalities, intellectual disability predisposition to malignancies. It caused by heterozygous germline HRAS mutations mostly affecting Gly12 or Gly13, which impair HRAS-GTPase activity result in increased downstream signal flow independent of incoming signals. Functional analyses rarer identified individuals with attenuated phenotypes revealed altered GDP/GTP...
The 'RASopathies' are a group of disorders sharing many clinical features and common pathophysiology. In this study, we aimed to clinically evaluate Turkish patients elucidate the underlying genetic etiology. Thirty-one with diagnosis one RASopathy syndromes were included in study. Of these, 26 (83.8%) had Noonan syndrome, whereas 5 either Costello, LEOPARD or cardio-facio-cutaneous syndromes. Twenty 31 (64.5%) found be mutation positive. Mutations PTPN11, SOS1 SHOC2 genes detected syndrome...
Fetal hydrops, fetal pleural effusions, hydrothorax, and chylothorax, may be associated with various genetic disorders, in particular the Noonan, cardio‐facio‐cutaneous Costello syndromes. These syndromes, collectively called RASopathies, are caused by mutations RAS/MAPK pathway, which is known to play a major role lymphangiogenesis. Recently, germline Casitas B‐cell lymphoma ( CBL ) gene were reported 25 patients of these, 20 had juvenile myelomonocytic leukemia (JMML). The disorder was...
Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties belongs to the RASopathies, a group of neurodevelopmental disorders caused germline mutations in genes encoding components RAS‐MAPK pathway. Mutations RAF1 gene are associated with syndrome, high prevalence hypertrophic cardiomyopathy (HCM). cluster exons conserved region 2 (CR2), kinase activation segment CR3 domain, C‐terminus. We present...
The RASopathies comprise a group of clinically overlapping developmental syndromes the common pathogenetic basis which is dysregulated signal flow through RAS-MAPK pathway. Mutations in several components or modifiers pathway have been identified Noonan syndrome and related disorders. Over past years copy number variants (CNVs) encompassing RAS genes (PTPN11, RAF1, MEK2, SHOC2) reported children with syndromes. These observations raised speculations that associated phenotypes represent...
ABSTRACT Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder belonging to the group of RASopathies. It typically characterized by congenital heart defects, short stature, dysmorphic craniofacial features, intellectual disability, failure thrive, and ectodermal abnormalities such as hyperkeratosis sparse, brittle, curly hair. CFC caused dominant mutations in one four genes BRAF , MEK1 MEK2 KRAS . Only three familial cases have been reported date, whereas vast majorities are...
Abstract RASopathies are a group of disorders caused by pathogenic variants in the genes encoding Ras/mitogen‐activated protein kinase pathway and share overlapping clinical molecular features. This study is aimed to describe features 38 patients with RASopathies. Sanger or targeted next‐generation sequencing related multiplex ligation‐dependent‐probe amplification analysis for NF1 were performed. The variant detection rate was 94.4%. While PTPN11 responsible 50% 18 Noonan syndrome (NS),...
Abstract Noonan syndrome‐like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group clinically related developmental disorders caused by germline mutations in genes that encode components acting RAS/MAPK pathway. Among NS/LAH (OMIM 607721) an extremely rare, multiple anomaly syndrome characterized dysmorphic facial features similar to those observed along some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow‐growing hair. ADA2...
The RASopathies constitute a diverse group of congenital disorders characterised by short stature, cardiac anomalies, distinctive facial features, predisposition to developing juvenile myelomonocytic leukaemia (JMML) and germline mutations in the Ras-mitogen activated protein kinase (MAPK) pathway.1 We recently described genomic landscape JMML, which can arise context or somatic lesions Ras-MAPK pathway identified RRAS2 as novel lesion JMML.2 thus hypothesised that could be an additional...
Abstract Objective Growth hormone (GH) deficiency (GHD) is commonly treated with recombinant human GH (rhGH). Individual response to rhGH therapy varies widely and there evidence that variations in growth-related genes, e. g. the receptor (GHR) gene, may impact treatment response. We aimed identify genetic polymorphisms which could serve as predictive markers of therapy. Methods conducted a analysis single nucleotide (SNPs) GHR exon 3 deletion 101 paediatric GHD patients receiving rhGH....
Germline PTPN11 mutations cause Noonan syndrome (NS), the most common disorder among RASopathies. encodes SHP2, a protein tyrosine-phosphatase controlling signaling through RAS-MAPK and PI3K-AKT pathways. Generally, NS-causing are missense changes destabilizing inactive conformation of or enhancing its binding to partners. Here, we report on two variants resulting in deletion duplication one three adjacent glutamine residues (Gln255 -to-Gln257 ). While p.(Gln257dup) caused typical NS...
Noonan syndrome (NS) and related disorders, which are now summarized under the term RASopathies, caused by germline mutations in genes encoding protein components of Ras/mitogen-activated kinase pathway. In this study, we evaluated clinical molecular spectrum 21 Tunisian patients, recruited a cardiology unit, for whom RASopathy diagnosis was suspected geneticists. Overall, 19 patients had NS 2 were classified as having Cardiofaciocutaneous (CFC) syndrome. 52% (n = 11) has been molecularly...