Evidence map›Paper›PMID 38538566›Full record

ArticleHuman molecular genetics2024

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

Nathalie P de Wagenaar, Lisa M van den Bersselaar, Hanny J H M Odijk, Sanne J M Stefens, Dieter P Reinhardt, Jolien W Roos-Hesselink, Roland Kanaar, Judith M A Verhagen, Hennie T Brüggenwirth, Ingrid M B H van de Laar and 2 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human molecular genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
1.1field-weighted citation impact, top 21% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 2 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 2 institutions in 2 countries.

Nathalie P de WagenaarDepartment of Molecular Genetics, Oncode Institute, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Lisa M van den BersselaarDepartment of Clinical Genetics and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.ORCID 0000-0002-1195-6054
Hanny J H M OdijkDepartment of Molecular Genetics, Oncode Institute, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Sanne J M StefensDepartment of Molecular Genetics, Oncode Institute, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Dieter P ReinhardtFaculty of Medicine and Health Sciences, McGill University, 3640 University Street, Montreal, QC H3A 0C7, Canada.
Jolien W Roos-HesselinkDepartment of Cardiology and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Roland KanaarDepartment of Molecular Genetics, Oncode Institute, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Judith M A VerhagenDepartment of Clinical Genetics and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Hennie T BrüggenwirthDepartment of Clinical Genetics and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Ingrid M B H van de LaarDepartment of Clinical Genetics and European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Ingrid van der PluijmDepartment of Molecular Genetics, Oncode Institute, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Jeroen EssersDepartment of Molecular Genetics, Oncode Institute, Erasmus MC, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Erasmus MC · NLMcGill University Health Centre · CA

Funding

Erasmus MC Mrace
6 · The paper itself

Abstract

rationalePathogenic (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.

objectivesInvestigate 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.

methodsA 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.

resultsIndividuals 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.

conclusionDistinguishing 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.

Indexed as

FibroblastsGenetic Association StudiesLoeys-Dietz SyndromeMuscle, Smooth, VascularSmad3 ProteinAdultCell DifferentiationCell LineFemaleHumansMaleMiddle AgedMutationMyocytes, Smooth MuscleMyofibroblastsPhenotypeSmad3 ProteinSMAD3 protein, humananeurysmsosteoarthritis syndromefunctional assayLoeys-Dietz syndromeSMAD3

Identifiers

PMID38538566
PMCPMC11153339
OpenAlexW4393276294

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.