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19 p.-6 fig. Plumitallo. Sara et al., Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disease, with an autosomal dominant inheritance and a worldwide incidence of about 1: 5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG or ACVRL1, which code for ENDOGLIN and Activin A Receptor Type II-Like Kinase 1 (ALK1), belonging to the TGF-β/BMP signalling pathway. Typical HHT clinical features are mucocutaneous telangiectases, arteriovenous malformations, spontaneous and recurrent epistaxis, as well as gastrointestinal bleedings. An additional, but less frequent, clinical manifestation in some HHT patients is the presence of Pulmonary Arterial Hypertension (PAH). The aim of this work is to describe the functional role of a novel ENG intronic variant found in a patient affected by both HHT and PAH, in order to assess whether it has a pathogenic role. We proved that the variant lies in a novel binding-site for the transcription factor Sp1, known to be involved in the regulation of ENG and ACVRL1 transcription. We confirmed a pathogenic role for this intronic variant, as it significantly reduces ENG transcription by affecting this novel Sp1 binding-site., This work was supported by grants from the Ministerio de Industria, Economia y Competitividad (SAF2013-43421-R to CB) and the Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER; ISCIII-CB06/07/0038 and ER16PIAC707 to CB) in Spain, both supported by European Regional Development Funds (FEDER). CIBERER is an initiative of the Instituto de Salud Carlos III (ISCIII) in Spain. This work is part of the results of research activity by SP, who holds a research fellowship (2/R.C./2016, n.20160028774) from the IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.

In 2011, classical genome-wide linkage studies and positional cloning successfully identified a new gene involved in both syndromic and nonsyndromic forms of aortic aneurysms—namely, the SMAD3 gene. The SMAD3 gene plays a role in signal transmission in the transforming growth factor-beta (TGF-β) pathway. Heterozygous loss-of-function mutations in the SMAD3 gene lead to a paradoxical enhancement of aortic wall TGF-β signaling. The TGF-β signaling pathway and its implication in the pathogenesis of aortic aneurysms are examined in detail in this chapter.

Heritable and idiopathic pulmonary arterial hypertension (PAH), together formerly known as primary pulmonary hypertension (PPH; Online Mendelian Inheritance in Man [OMIM] 178600), are clinically identical progressive disorders characterized by elevated pulmonary artery pressure with pathologic changes originating in the precapillary pulmonary arteries. BMPR2 is the gene encoding bone morphogenetic protein receptor type II (BMPR2; OMIM 600799 ), which is mutated in over 75% of families with PAH. The BMPR2 gene's association with PAH, as well as the rare association of mutations in other members of the transforming growth factor β superfamily of receptors with PAH (ACVRL1 and ENG), provides insights into disease pathogenesis and risk calculation. These insights augment a growing interest in understanding the factors which make genetically, and other, susceptible individuals resilient to PAH.

Publisher Summary This chapter focuses on the mechanisms of action of transforming growth factor- β (TGF- β ) and related factors, and in particular on their interaction with specific receptors and binding proteins. TGF- β was initially purified from human platelets as a 25-kDa homodimeric peptide using the ability of the factor to confer morphological transformation and anchorage-independent growth of normal rat kidney (NRK) fibroblasts as an assay. The biological effects that are mediated by TGF- β include regulation of cell proliferation, differentiation, adhesion, and migration; stimulation of extracellular matrix (ECM) deposition; and modulation of many inflammatory and immune responses. TGF- β has been proposed to have important in vivo physiological roles in tissue recycling, wound repair, and morphogenesis during embryogenic development. Three distinct TGF- β isoforms have been identified in mammals; denoted TGF β 1, TGF- β 2, and TGF- β 3, and they exert similar, but not identical, biological activities in vitro as well as in vivo. The cellular action of TGF- β is mediated through binding to cell surface receptors. The action of TGF- β is carefully controlled. TGF- β s are secreted from cells as latent forms that are activated under certain conditions.

Transforming growth factor (TGF)- β plays essential roles in embryogenesis, particularly during periods of morphogenesis. Some of the same embryological mechanisms are reiterated in the adult during the normal processes of tissue remodeling and repair and aberrantly in various pathological processes, including carcinogenesis. This chapter highlights the new advances in the understanding of the complex biology of TGF- β and discusses the chemistry of TGF- β . The broad range of biological activities of TGF- β makes it highly likely that other peptide activities—purified by presumably novel and specific assays—will result from TGF- β once their amino acid sequence is determined. TGF- β 1 and 2 are two homologous forms of a homodimeric peptide with molecular weight of 25,000. Every chain of the peptide contains 112 amino acids of which nine are cysteine residues. The chapter reviews the structure of TGF- β 1 and 2 and TGF- β gene family. The biological activities of the members of the TGF- β family are described in the chapter. The chapter further reviews the regulation of gene activity by TGF- β, antibodies to TGF- β , and role of TGF- β in embryogenesis, tissue repair and remodeling, and carcinogenesis and other proliferative diseases.