Search

Your search keyword '"Odijk HJHM"' showing total 2 results
Start Over Author "Odijk HJHM"
2 results on '"Odijk HJHM"'

1. Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation

Author

de Wagenaar, NP, van den Bersselaar, LM, Odijk, HJHM, Stefens, SJM, Reinhardt, DP, Roos-Hesselink, JW, Kanaar, R, Verhagen, JMA, Brueggenwirth, HT, van de Laar, IMBH, van der Pluijm, I, Essers, J, de Wagenaar, NP, van den Bersselaar, LM, Odijk, HJHM, Stefens, SJM, Reinhardt, DP, Roos-Hesselink, JW, Kanaar, R, Verhagen, JMA, Brueggenwirth, HT, van de Laar, IMBH, van der Pluijm, I, and Essers, J

Abstract

Rationale Pathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis. Objectives Investigate the impact of P/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants. Methods A retrospective analysis on clinical data from individuals with a P/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts. Results Individuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P = 0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0 years [IQR 29.0–47.0] in individuals with DN variants in MH2, compared to 46.0 years [IQR 40.0–54.0] in those with HI variants (P = 0.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines. Conclusion Distinguishing between P/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs.

Published
2024

2. Functional analysis of cell lines derived from SMAD3-related Loeys-Dietz syndrome patients provides insights into genotype-phenotype relation.

Author

de Wagenaar NP, van den Bersselaar LM, Odijk HJHM, Stefens SJM, Reinhardt DP, Roos-Hesselink JW, Kanaar R, Verhagen JMA, Brüggenwirth HT, van de Laar IMBH, van der Pluijm I, and Essers J

Subjects
Humans, Male, Female, Adult, Middle Aged, Cell Differentiation genetics, Cell Line, Myocytes, Smooth Muscle metabolism, Retrospective Studies, Phenotype, Myofibroblasts metabolism, Myofibroblasts pathology, Mutation, Smad3 Protein genetics, Smad3 Protein metabolism, Loeys-Dietz Syndrome genetics, Loeys-Dietz Syndrome pathology, Fibroblasts metabolism, Genetic Association Studies, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology
Abstract

Rationale: Pathogenic (P)/likely pathogenic (LP) SMAD3 variants cause Loeys-Dietz syndrome type 3 (LDS3), which is characterized by arterial aneurysms, dissections and tortuosity throughout the vascular system combined with osteoarthritis., Objectives: Investigate the impact of P/LP SMAD3 variants with functional tests on patient-derived fibroblasts and vascular smooth muscle cells (VSMCs), to optimize interpretation of SMAD3 variants., Methods: A retrospective analysis on clinical data from individuals with a P/LP SMAD3 variant and functional analyses on SMAD3 patient-derived VSMCs and SMAD3 patient-derived fibroblasts, differentiated into myofibroblasts., Results: Individuals with dominant negative (DN) SMAD3 variant in the MH2 domain exhibited more major events (66.7% vs. 44.0%, P = 0.054), occurring at a younger age compared to those with haploinsufficient (HI) variants. The age at first major event was 35.0 years [IQR 29.0-47.0] in individuals with DN variants in MH2, compared to 46.0 years [IQR 40.0-54.0] in those with HI variants (P = 0.065). Fibroblasts carrying DN SMAD3 variants displayed reduced differentiation potential, contrasting with increased differentiation potential in HI SMAD3 variant fibroblasts. HI SMAD3 variant VSMCs showed elevated SMA expression and altered expression of alternative MYH11 isoforms. DN SMAD3 variant myofibroblasts demonstrated reduced extracellular matrix formation compared to control cell lines., Conclusion: Distinguishing between P/LP HI and DN SMAD3 variants can be achieved by assessing differentiation potential, and SMA and MYH11 expression. The differences between DN and HI SMAD3 variant fibroblasts and VSMCs potentially contribute to the differences in disease manifestation. Notably, myofibroblast differentiation seems a suitable alternative in vitro test system compared to VSMCs., (© The Author(s) 2024. Published by Oxford University Press.)

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results