transforming-growth-factor-beta and Genetic-Diseases--Inborn

Thrombocytopenia with absent radii (TAR) syndrome is a rare autosomal recessive disease characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia. Its expression includes skeletal, hematologic, and cardiac system abnormalities. According to some authors, the association of disparate skeletal and hematologic abnormalities is related to simultaneous development of the heart, radii, and megakaryocytes at 6 to 8 weeks' gestation. Thrombocytopenia that generally presents at birth or during the neonatal period can also occur subsequently. Data as to the physiopathology of TAR syndrome are scanty because of the low frequency of the disease and frequent unavailability of samples for bone marrow. The few studies on colony formation suggest that thrombocytopenia could be due to a decreased response to thrombopoietin that affects both proliferation and differentiation. The genetic basis of this syndrome remains unclear because c-mpl gene mutations are not a likely cause of thrombocytopenia and they are also frequent in the normal population. This is also the case for the mutations to the multifunctional growth factor transforming growth factor (TGF)-beta2 gene as described in our laboratory. Finally, the deletion on chromosome 1q21.1 described by Klopocki and colleagues is not considered sufficient to determine the TAR syndrome phenotype. We have reported that bone marrow adherent stromal cells from patients with TAR syndrome do not express CD105 antigen (expressed in normal mesenchymal cells), part of the receptor complex for TGF-beta1 and TGF-beta3. Thus, the hypothesis that the clinical phenotype of TAR could derive from damage to a common osteo/chondrogenic and hemopoietic progenitor warrants further study.

Topics: Abnormalities, Multiple; Antigens, CD; Bone Marrow; Chromosome Deletion; Chromosomes, Human, Pair 1; Endoglin; Gene Expression Regulation; Genetic Diseases, Inborn; Hematopoietic Stem Cells; Humans; Megakaryocytes; Receptors, Cell Surface; Stromal Cells; Syndrome; Thrombocytopenia; Thrombopoietin; Transforming Growth Factor beta

Transforming growth factor beta (TGF-beta) superfamily signaling pathways are ubiquitous and essential regulators of cellular processes including proliferation, differentiation, migration, and survival, as well as physiological processes, including embryonic development, angiogenesis, and wound healing. Alterations in these pathways, including either germ-line or somatic mutations or alterations in the expression of members of these signaling pathways often result in human disease. Appropriate regulation of these pathways is required at all levels, particularly at the ligand level, with either a deficiency or an excess of specific TGF-beta superfamily ligands resulting in human disease. TGF-beta superfamily ligands and members of these TGF-beta superfamily signaling pathways also have emerging roles as diagnostic, prognostic or predictive markers for human disease. Ongoing studies will enable targeting of TGF-beta superfamily signaling pathways for the chemoprevention and treatment of human disease.

Topics: Biomarkers; Cardiovascular Diseases; Chromosome Aberrations; Disease; Female; Genetic Diseases, Inborn; Humans; Ligands; Musculoskeletal Diseases; Mutation; Neoplasms; Pregnancy; Pregnancy Complications; Prognosis; Signal Transduction; Transforming Growth Factor beta

The transforming growth factor beta (TGFbeta) signaling pathway regulates several biological processes including cellular proliferation, differentiation, apoptosis, migration, and extracellular matrix deposition. Ligand and receptor family members signal through two main Smad signaling branches, TGFbeta/activin to Smad2/3 (Sma and MAD-related proteins) and bone morphogenetic protein (BMP) to Smad1/5. At the molecular level, TGFbeta acts by modifying cytoskeletal organization and ultimately regulating expression of specific target genes. Germline disruption of TGFbeta signaling leads to several types of hereditary congenital malformation or dysfunction of the skeletal, muscular and/or cardiovascular systems, and to cancer predisposition syndromes. In this review, the molecular etiology of TGFbeta-associated disorders is examined, together with a discussion of clinical overlap between syndromes and possible biological explanations underlying the variable penetrance and expressivity of clinical characteristics. Increasing our understanding of the molecular etiology underlying genotype-phenotype correlations will ultimately provide a molecular-based approach that should result in better prognostic tools, smart therapeutics and individualized disease management, not only for these rare syndromes, but for more generalized disorders of the cardiovascular and musculoskeletal systems and cancer. The clinical consequence of TGFbeta signaling mutations appears to depend on environmental factors and on the basal levels of ongoing signaling transduction networks specific to each individual. In this respect, genetic background might be a central factor in determining disease outcome and treatment strategy for TGFbeta-associated diseases.

Topics: Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Mutation; Neoplasms; Signal Transduction; Transforming Growth Factor beta

Topics: Activating Transcription Factor 2; Animals; Animals, Genetically Modified; Cell Differentiation; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; DNA-Binding Proteins; Drosophila Proteins; Embryonic Development; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genetic Diseases, Inborn; Genome; Humans; Mice; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-maf; Signal Transduction; Smad2 Protein; Trans-Activators; Transcription Factors; Transcription, Genetic; Transforming Growth Factor beta

Topics: Cell Differentiation; Cell Division; Genetic Diseases, Inborn; Humans; Models, Biological; Neoplasms; Signal Transduction; Transforming Growth Factor beta

The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

Topics: Biological Transport; DNA-Binding Proteins; Gene Expression Regulation; Genetic Diseases, Inborn; Humans; Neoplasms; Protein Serine-Threonine Kinases; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad1 Protein; Trans-Activators; Transforming Growth Factor beta

Topics: Animals; Drosophila Proteins; Gene Expression Regulation, Developmental; Genetic Diseases, Inborn; Glial Cell Line-Derived Neurotrophic Factor; Glial Cell Line-Derived Neurotrophic Factor Receptors; Hirschsprung Disease; Humans; Mice; Mice, Transgenic; Nerve Growth Factors; Nerve Tissue Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases; Signal Transduction; Transforming Growth Factor beta

Development of the aorta and pulmonary artery is a complex process involving multiple molecular genetic pathways that modulate morphogenesis of the outflow tracts and the anastomosis of branch vessels. Recent genetic studies of the cardiovascular system demonstrate that congenital and adult onset progressive disorders of the great vessels such as aneurysms are components of generalized vascular, cardiac, and extracardiovascular syndromes. Current paradigms suggest that aortic disease is founded in patterning anomalies of the conotruncus that occur in utero. These aberrations can be consequences of genetic aberrations in transcriptional regulation of signal transduction both within and outside the developing great vessels.

Topics: Blood Vessels; Electrophysiology; Genetic Diseases, Inborn; Heart Defects, Congenital; Humans; Phenotype; Signal Transduction; Transforming Growth Factor beta