A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

Dorien Schepers¹, Giada Tortora^{2

3}, Hiroko Morisaki^{4

5

6}, Gretchen MacCarrick⁷, Mark Lindsay⁸, David Liang⁹, Sarju G Mehta¹⁰, Jennifer Hague¹⁰, Judith Verhagen¹¹, Ingrid van de Laar¹¹, Marja Wessels¹¹, Yvonne Detisch¹², Mieke van Haelst^{13

14}, Annette Baas¹³, Klaske Lichtenbelt¹³, Kees Braun¹⁵, Denise van der Linde¹⁶, Jolien Roos-Hesselink¹⁶, George McGillivray¹⁷, Josephina Meester¹, Isabelle Maystadt¹⁸, Paul Coucke¹⁹, Elie El-Khoury²⁰, Sandhya Parkash²¹, Birgitte Diness²², Lotte Risom²², Ingrid Scurr²³, Yvonne Hilhorst-Hofstee²⁴, Takayuki Morisaki^{4

5}, Julie Richer²⁵, Julie Désir²⁶, Marlies Kempers²⁷, Andrea L Rideout²⁸, Gabrielle Horne²⁹, Chris Bennett³⁰, Elisa Rahikkala³¹, Geert Vandeweyer¹, Maaike Alaerts¹, Aline Verstraeten¹, Hal Dietz⁷, Lut Van Laer¹, Bart Loeys^{1

27}

Affiliations

¹ Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
² Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy.
³ Department of Molecular and Clinical Sciences, Marche Polytechnic University, Ancona, Italy.
⁴ Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
⁵ Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan.
⁶ Department of Medical Genetics, Sakakibara Heart Institute, Tokyo, Japan.
⁷ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁸ Thoracic Aortic Center, Departments of Medicine and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston.
⁹ Cardiovascular Medicine, Stanford University Medical Center, Stanford, California.
¹⁰ East Anglian Regional Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK.
¹¹ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹² Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
¹³ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁴ Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
¹⁵ Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁶ Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁷ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁸ Centre de Génétique Humaine, Institut de Pathologie et de Génétique (IPG), Gosselies (Charleroi), Belgium.
¹⁹ Center for Medical Genetics, Ghent University Hospital and Ghent University, Ghent, Belgium.
²⁰ Department of Diagnostic Cardiology, Clinique St Luc, Bouge (Namur), Belgium.
²¹ Department of Pediatrics, Maritime Medical Genetics Service, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
²² Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²³ Department of Clinical Genetics, St. Michael's Hospital, Bristol, UK.
²⁴ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ Department of Medical Genetics, Children's Hospital of Eastern Ontario, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
²⁶ Centre de Génétique Humaine, Hôpital Erasme, Université Libre de Bruxelles, Belgium.
²⁷ Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
²⁸ Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
²⁹ Department of Medicine (Cardiology) and School of Biomedical Engineering, Dalhousie University, Halifax, Nova Scotia, Canada.
³⁰ Department of Clinical Genetics, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
³¹ Department of Clinical Genetics, Oulu University Hospital, University of Oulu, Oulu, Finland.

PMID: 29392890
PMCID: PMC5947146
DOI: 10.1002/humu.23407

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

Dorien Schepers et al. Hum Mutat. 2018 May.

. 2018 May;39(5):621-634.

doi: 10.1002/humu.23407. Epub 2018 Mar 6.

Authors

Affiliations

¹ Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
² Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy.
³ Department of Molecular and Clinical Sciences, Marche Polytechnic University, Ancona, Italy.
⁴ Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
⁵ Department of Molecular Pathophysiology, Osaka University Graduate School of Pharmaceutical Sciences, Suita, Osaka, Japan.
⁶ Department of Medical Genetics, Sakakibara Heart Institute, Tokyo, Japan.
⁷ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁸ Thoracic Aortic Center, Departments of Medicine and Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston.
⁹ Cardiovascular Medicine, Stanford University Medical Center, Stanford, California.
¹⁰ East Anglian Regional Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK.
¹¹ Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹² Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
¹³ Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁴ Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
¹⁵ Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁶ Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
¹⁷ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁸ Centre de Génétique Humaine, Institut de Pathologie et de Génétique (IPG), Gosselies (Charleroi), Belgium.
¹⁹ Center for Medical Genetics, Ghent University Hospital and Ghent University, Ghent, Belgium.
²⁰ Department of Diagnostic Cardiology, Clinique St Luc, Bouge (Namur), Belgium.
²¹ Department of Pediatrics, Maritime Medical Genetics Service, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
²² Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
²³ Department of Clinical Genetics, St. Michael's Hospital, Bristol, UK.
²⁴ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ Department of Medical Genetics, Children's Hospital of Eastern Ontario, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
²⁶ Centre de Génétique Humaine, Hôpital Erasme, Université Libre de Bruxelles, Belgium.
²⁷ Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
²⁸ Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
²⁹ Department of Medicine (Cardiology) and School of Biomedical Engineering, Dalhousie University, Halifax, Nova Scotia, Canada.
³⁰ Department of Clinical Genetics, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
³¹ Department of Clinical Genetics, Oulu University Hospital, University of Oulu, Oulu, Finland.

PMID: 29392890
PMCID: PMC5947146
DOI: 10.1002/humu.23407

Abstract

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.

Keywords: Loeys-Dietz syndrome; SMAD2; SMAD3; TGFB2; TGFB3; aneurysm.

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Figures

**Figure 1**
Schematic representation of the *SMAD2* and *SMAD3* gene with their protein coding domains. Boxes represent exons 1–11 and 1–9, respectively. On the left side of the schematic are the previously reported mutations, whereas on the right side mutations identified in this study are described. For *SMAD2*, the first depicted exon is exon 2 because exon 1 is 5′UTR. Mutations are annotated at the protein level, with exception of splice site mutations (reference transcript: NM_005901.5 and NM_005902.3 for *SMAD3*)

**Figure 2**
Schematic representation of the *TGFB2* and *TGFB3* gene with their protein coding domains. Boxes represent exons 1–8 and 1–7, respectively. On the left side of the schematic are the previously reported mutations, whereas on the right side mutations identified in this study are described. Mutations are annotated at the protein level (reference transcript: NM_001135599.2 for *TGFB2* and NM_003239.3 for *TGFB3*)

**Figure 3**
Frequencies of the different types of *SMAD2*, *SMAD3*, *TGFB2*, and *TGFB3* mutations identified so far

See this image and copyright information in PMC

References

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A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

Affiliations

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases