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Genetic Disorders of the TGFβ Signaling Family
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Genetic Disorders of the TGFβ Signaling Family

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (25 October 2020) | Viewed by 7604

Special Issue Editor

Prof. Dr. Rosemary J. Akhurst

E-Mail Website
Guest Editor
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA
Interests: TGFβ superfamily; human genetic disorders; BMP; GDF; activin; myostatin

Special Issue Information

Dear Colleagues,

The TGFβ superfamily of signaling molecules, in humans, includes over 30 ligands that are clustered into several sub-families, all that signal through one or more of the five type II receptors (TGFβR2, ACVR2, ACVR2B, BMPR2, and AMHR2), seven type I receptors (ACVRL1/Alk1, ACVR1/Alk2, BMPR1A/Alk3, ACVR1B/Alk4,TGFβR1/ Alk5, BMPR1B/Alk6, and ACVR1C/Alk7), five receptor-associated Smad signal transducers, Smad1, Smad2, Smad3, Smad5 and Smad8, and a single Smad4 nucleocytoplasmic shuttling co-Smad, Smad4. These signaling pathways play critical roles in embryonic development and are frequently perturbed in common disease processes such as cancer, cardiovascular disease and immunity, and drugs that target pathway components have been developed for therapeutic purposes. Gain- or loss-of-function mutations in pathway components cause various human genetic disorders that manifest as abnormal patterns of skeletal-muscular growth and dysmorphology, as well as cardiovascular and premalignant syndromes. This Special Issue of Genes, entitled “Genetic Disorders of the TGFβ Signaling Family”, will focus on human genetic disorders caused by mutations in components of the TGFβ signaling superfamily, the novel molecular mechanistic insights gained from study of these genetic disorders, and therapeutic approaches developed for their treatment. It will provide an overview of recent developments in specialized research topics and critical perspectives on upcoming challenges.

Prof. Rosemary J. Akhurst
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • TGFβ superfamily
  • human genetic disorders
  • BMP
  • GDF
  • activin
  • myostatin

Published Papers (2 papers)

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Review

14 pages, 5571 KiB  
Review
Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions
by Ryan O. Snodgrass, Timothy J. A. Chico and Helen M. Arthur
Genes 2021, 12(2), 174; https://doi.org/10.3390/genes12020174 - 27 Jan 2021
Cited by 31 | Viewed by 4307
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller [...] Read more.
Hereditary haemorrhagic telangiectasia (HHT) is characterised by arteriovenous malformations (AVMs). These vascular abnormalities form when arteries and veins directly connect, bypassing the local capillary system. Large AVMs may occur in the lungs, liver and brain, increasing the risk of morbidity and mortality. Smaller AVMs, known as telangiectases, are prevalent on the skin and mucosal lining of the nose, mouth and gastrointestinal tract and are prone to haemorrhage. HHT is primarily associated with a reduction in endoglin (ENG) or ACVRL1 activity due to loss-of-function mutations. ENG and ACVRL1 transmembrane receptors are expressed on endothelial cells (ECs) and bind to circulating ligands BMP9 and BMP10 with high affinity. Ligand binding to the receptor complex leads to activation of the SMAD1/5/8 signalling pathway to regulate downstream gene expression. Various genetic animal models demonstrate that disruption of this pathway in ECs results in AVMs. The vascular abnormalities underlying AVM formation result from abnormal EC responses to angiogenic and haemodynamic cues, and include increased proliferation, reduced migration against the direction of blood flow and an increased EC footprint. There is growing evidence that targeting VEGF signalling has beneficial outcomes in HHT patients and in animal models of this disease. The anti-VEGF inhibitor bevacizumab reduces epistaxis and has a normalising effect on high cardiac output in HHT patients with hepatic AVMs. Blocking VEGF signalling also reduces vascular malformations in mouse models of HHT1 and HHT2. However, VEGF signalling is complex and drives numerous downstream pathways, and it is not yet clear which pathway (or combination of pathways) is critical to target. This review will consider the recent evidence gained from HHT clinical and preclinical studies that are increasing our understanding of HHT pathobiology and informing therapeutic strategies. Full article
(This article belongs to the Special Issue Genetic Disorders of the TGFβ Signaling Family)
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12 pages, 1960 KiB  
Review
Multiple Self-Healing Squamous Epithelioma (MSSE): A Digenic Trait Associated with Loss of Function Mutations in TGFBR1 and Variants at a Second Linked Locus on the Long Arm of Chromosome 9
by David Goudie
Genes 2020, 11(12), 1410; https://doi.org/10.3390/genes11121410 - 26 Nov 2020
Cited by 11 | Viewed by 3033
Abstract
MSSE (Ferguson-Smith disease) is a rare familial condition in which multiple skin tumors resembling squamous carcinomas invade locally and then regress spontaneously after several months, leaving disfiguring scars. We review evidence from haplotype studies in MSSE families with common ancestry that the condition [...] Read more.
MSSE (Ferguson-Smith disease) is a rare familial condition in which multiple skin tumors resembling squamous carcinomas invade locally and then regress spontaneously after several months, leaving disfiguring scars. We review evidence from haplotype studies in MSSE families with common ancestry that the condition is caused by loss of function mutations in TGFBR1 interacting with permissive variants at a second linked locus on the long arm of chromosome 9. The spectrum of TGFBR1 mutations in MSSE and the allelic disorder Loeys Dietz syndrome (characterized by developmental anomalies and thoracic aortic aneurysms) differ. Reports of patients with both MSSE and Loeys Dietz syndrome are consistent with variants at a second locus determining whether self-healing epitheliomas occur in patients with the loss of function mutations found in most MSSE patients or the missense mutations in the intracellular kinase domain of TGFBR1 that characterize Loeys Dietz syndrome. Full article
(This article belongs to the Special Issue Genetic Disorders of the TGFβ Signaling Family)
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