Genomic Observations of a Rare/Pathogenic SMAD3 Variant in Loeys⁻Dietz Syndrome 3 Confirmed by Protein Informatics and Structural Investigations.

John E Richter,Thomas R Caulfield,Haytham Helmi,Charitha Vadlamudi,Paldeep S Atwal,Ahmed N Mohammad,Klaas Wierenga,Ayesha Samreen,Stephanie Hines

doi:10.3390/medicina55050137

Abstract

Background and objectives: Loeys–Dietz syndrome 3, also known as aneurysms-–osteoarthritis syndrome, is an autosomal dominant genetic connective tissue disease caused by pathogenic variants in SMAD3, a transcription factor involved in TGF-β signaling. This disorder is characterized by early-onset osteoarthritis and arterial aneurysms. Common features include scoliosis, uvula abnormalities, striae, and velvety skin. Materials and Methods: The pathogenicity of a variant of uncertain significance in the SMAD3 gene was evaluated (variant c.220C > T) through personalized protein informatics and molecular studies. Results: The case of a 44-year-old male, who was originally presumed to have Marfan syndrome, is presented. An expanded gene panel determined the probable cause to be a variant in SMAD3, c.220C > T (p.R74W). His case was complicated by a history of stroke, but his phenotype was otherwise characteristic for Loeys–Dietz syndrome 3. Conclusion: This case emphasizes the importance of comprehensive genetic testing to evaluate patients for connective tissue disorders, as well as the potential benefit of utilizing a protein informatics platform for the assessment of variant pathogenicity.

Highlights

SMAD family member 3 (SMAD3), known as mothers against decapentaplegic homolog 3, is a protein encoded at locus 15q22.33 that is implicated in transforming growth factor-beta (TGF-β) signaling (OMIM*603109)
The consequences of improper TGF-β signaling are reflected in Loeys–Dietz syndrome 3 (LDS3) (OMIM#613795), a multisystem connective tissue disorder caused by pathogenic variants of SMAD3 [2]
Examinations of the trimer reveal an interaction zone that consists of residues, shown in Figure 1C–D, that forms a pore-like circular interface (Figure 1C–D). These residues are known to be critical for the formation of SMAD4 heterodimerization contacts, which is crucial for the function in transcription regulation (Figure 1D)

Summary

Introduction

SMAD family member 3 (SMAD3), known as mothers against decapentaplegic homolog 3, is a protein encoded at locus 15q22.33 that is implicated in transforming growth factor-beta (TGF-β) signaling (OMIM*603109). The consequences of improper TGF-β signaling are reflected in Loeys–Dietz syndrome 3 (LDS3) (OMIM#613795), a multisystem connective tissue disorder caused by pathogenic variants of SMAD3 [2]. Loeys–Dietz syndrome 3, known as aneurysms—osteoarthritis syndrome, is an autosomal dominant genetic connective tissue disease caused by pathogenic variants in SMAD3, a transcription factor involved in TGF-β signaling. This disorder is characterized by early-onset osteoarthritis and arterial aneurysms. An expanded gene panel determined the probable cause to be a variant in SMAD3, c.220C > T (p.R74W) His case was complicated by a history of stroke, but his phenotype was otherwise characteristic for Loeys–Dietz syndrome 3. Conclusion: This case emphasizes the importance of comprehensive genetic testing to evaluate patients for connective tissue disorders, as well as the potential benefit of utilizing a protein informatics platform for the assessment of variant pathogenicity

Methods

Results

Discussion

Conclusion