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

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

doi:10.3390/medicina55050137

Cited by 5 publications

(2 citation statements)

References 38 publications

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“…Alphafold was examined for comparison where appropriate [25]. Our computational platform for in silico variant analyses has been extensively explored in recent years [26][27][28][29][30][31][32][33][34][35].…”

Section: Molecular Modelingmentioning

confidence: 99%

Statistical Mechanics Metrics in Pairing and Parsing In Silico and Phenotypic Data of a Novel Genetic NFκB1 (c.T638A) Variant

Chaudhri,

Abbott,

Islam

et al. 2023

Genes

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(1) Background: Mutations in NFκB1, a transcriptional regulator of immunomodulating proteins, are a known cause of inborn errors of immunity. Our proband is a 22-year-old male with a diagnosis of common variable immunodeficiency (CVID), cytopenias with massive splenomegaly, and nodular regenerative hyperplasia of the liver. Genetic studies identified a novel, single-point mutation variant in NFκB1, c. T638A p. V213E. (2) Methods: Next-generation panel sequencing of the patient uncovered a novel single-point mutation in the NFκB1 gene that was modeled using the I-TASSER homology-modeling software, and molecular dynamics were assessed using the YASARA2 software (version 20.14.24). (3) Results: This variant replaces valine with glutamic acid at position 213 in the NFκB1 sequence. Molecular modeling and molecular dynamic studies showed altered dynamics in and around the rel homology domain, ankyrin regions, and death domain of the protein. We postulate that these changes alter overall protein function. (4) Conclusions: This case suggests the pathogenicity of a novel variant using protein-modeling techniques and molecular dynamic simulations.

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Section: Molecular Modelingmentioning

confidence: 99%

Statistical Mechanics Metrics in Pairing and Parsing In Silico and Phenotypic Data of a Novel Genetic NFκB1 (c.T638A) Variant

Chaudhri,

Abbott,

Islam

et al. 2023

Genes

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“…LDS3 is characterized by aneurysms and tortuosity of the aorta and/or middle-sized arteries, accompanied by osteoarthritis (5,6). Currently, over 60 different P/LP variants in SMAD3 have been identified in LDS3 families (24)(25)(26)(27)(28), including missense, truncating and splicing variants, and intragenic and whole gene deletions (24,29,30). Interestingly, large phenotypic variation is described between LDS3 families, suggesting that, among others, genotype and ancestry might play a role.…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz Syndrome patients provides insights into genotype-phenotype relations

de Wagenaar,

van den Bersselaar,

Odijk

et al. 2023

Preprint

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IntroductionPathogenic (P) and likely pathogenic (LP) variants in theSMAD3gene cause Loeys-Dietz syndrome type 3 (LDS3), also known as aneurysms-osteoarthritis syndrome (AOS). The phenotype of LDS3 is highly variable and characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with skeletal, cutaneous and facial features.ObjectivesInvestigate the impact of P/LPSMAD3variants through conducting functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs).The resulting knowledge will optimize interpretation ofSMAD3variants.Material and methodsWe conducted a retrospective analysis on clinical data from individuals with a P/LPSMAD3variant and utilized patient-derived VSMCs to investigate the functional impacts of dominant negative (DN) and haploinsufficient (HI) variants in SMAD3. Additionally, to broaden our cell model accessibility, we performed similar functional analyses on patient-derived fibroblasts carrying SMAD3 variants, differentiating them into myofibroblasts with the same variants. This enabled us to study the functional effects of DN and HI variants inSMAD3across both patient-derived myofibroblasts and VSMCs.ResultsIndividuals with dominant negative (DN) variants in the MH2 protein interaction domain of SMAD3 exhibited a higher frequency of major events (66.7% vs. 44.0%, p=0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. Moreover, the age at the onset of the first major event was notably younger in individuals with DN variants in MH2, 35.0 years [IQR 29.0-47.0], compared to 46.0 years [IQR 40.0-54.0] in those with HI variants (p=0.065). In functional assays, fibroblasts carrying DNSMAD3variants displayed reduced differentiation potential, contrasting with increased differentiation potential observed in fibroblasts with HISMAD3variants. Additionally, HISMAD3variant VSMCs showed elevated SMA expression, while exhibiting altered expression of alternative MYH11 isoforms. Conversely, DNSMAD3variant myofibroblasts demonstrated reduced extracellular matrix (ECM) formation compared to control cell lines. These findings collectively indicate distinct functional consequences between DN and HI variants inSMAD3across fibroblasts and VSMCs, potentially contributing to the observed differences in disease manifestation and age of onset of major events.ConclusionDistinguishing between P/LP HI and DNSMAD3variants can be achieved by assessing differentiation potential, and evaluating SMA and MYH11 expression. Notably, myofibroblast differentiation seems to be a suitable alternative in vitro test system in comparison to VSMCs. Moreover, there is a notable trend of aortic events occurring at younger age in individuals with a DNSMAD3variant in the MH2 domain, distinguishing them from those with a DN variant in the MH1 domain or a HI variant.

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Audit of Gastrointestinal Manifestations in Patients with Loeys–Dietz Syndrome and Vascular Ehlers–Danlos Syndrome

et al. 2020

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

Cited by 5 publications

References 38 publications

Statistical Mechanics Metrics in Pairing and Parsing In Silico and Phenotypic Data of a Novel Genetic NFκB1 (c.T638A) Variant

Statistical Mechanics Metrics in Pairing and Parsing In Silico and Phenotypic Data of a Novel Genetic NFκB1 (c.T638A) Variant

Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz Syndrome patients provides insights into genotype-phenotype relations

Audit of Gastrointestinal Manifestations in Patients with Loeys–Dietz Syndrome and Vascular Ehlers–Danlos Syndrome

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