Evidence map›Paper›PMID 33661429›Full record

ArticleMolecular and cellular biochemistry2021

Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype.

Kathryn Volkening, Sali M K Farhan, Jessica Kao, Cheryl Leystra-Lantz, Lee Cyn Ang, Adam McIntyre, Jian Wang, Robert A Hegele, Michael J Strong

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

Article in Molecular and cellular biochemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
0.7field-weighted citation impact, top 29% 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

6 citing papers in PubMed, 8 citations in OpenAlex.

  1. Review
  2. Article
  3. Article
  4. Article
  5. Article
  6. R-Loop Immunoprecipitation: A Method to Detect R-Loop Interacting Factors.Methods in molecular biology (Clifton, N.J.) · 2022
    Article
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

9 authors at 2 institutions in 2 countries.

Kathryn VolkeningMolecular Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.ORCID http://orcid.org/0000-0002-7601-4869
Sali M K FarhanAnalytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.ORCID http://orcid.org/0000-0001-5936-0957
Jessica KaoMolecular Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Cheryl Leystra-LantzMolecular Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Lee Cyn AngDepartment of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.ORCID http://orcid.org/0000-0003-0940-4995
Adam McIntyreBlackburn Cardiovascular Genetics Lab, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.ORCID http://orcid.org/0000-0002-7836-5187
Jian WangBlackburn Cardiovascular Genetics Lab, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Robert A HegeleDepartment of Pathology and Laboratory Medicine, London Health Sciences Centre-University Hospital, London, ON, Canada.ORCID http://orcid.org/0000-0003-2861-5325
Michael J StrongMolecular Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. mstrong@uwo.ca.ORCID http://orcid.org/0000-0003-1988-6262
Western University · CABroad Institute · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), can be clinically heterogeneous which may be explained by the co-inheritance of multiple genetic variants that modify the clinical course. In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revealed a p.Gly602Ser variant in LMNA, and two additional variants, one each in SETX (g.intron10-13delCTT) and FUS (p.Gly167_Gly168del). These latter genes have been linked to ALS. All family members were genotyped and each variant, and each combination of variants detected, were functionally evaluated in vitro regarding effects on cell survival, expression patterns and cellular phenotype. Muscle biopsy retrieved from the individual with ALS showed leakage of chromatin from the nucleus, a phenotype that was recapitulated in vitro with expression of all three variants simultaneously. Individually expressed variants gave cellular phenotypes there were unremarkable. Interestingly the FUS variant appears to be protective against the effects of the SETX and the LMNA variants on cell viability and may indicate loss of interaction of FUS with SETX and/or R-loops. We conclude that these findings support genetic modifications as an explanation of the clinical heterogeneity observed in human disease.

Indexed as

Amyotrophic Lateral SclerosisDNA HelicasesLamin Type ALipodystrophyMultifunctional EnzymesMutation, MissenseRNA-Binding Protein FUSRNA HelicasesAmino Acid SubstitutionFamilyFemaleHEK293 CellsHumansMaleDNA HelicasesFUS protein, humanLamin Type ALMNA protein, humanMultifunctional EnzymesRNA-Binding Protein FUSRNA HelicasesSETX protein, humanAmyotrophic lateral sclerosisFused in sarcoma (FUS)Lamin A (LMNA)Nuclear membraneR-loopSenataxin (SETX)

Identifiers

PMID33661429
PMCPMC8192393
OpenAlexW3135196309

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.