Evidence map›Paper›PMID 29706353›Full record

ArticleAmerican journal of human genetics2018

Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms.

Thomas A Forbes, Sara E Howden, Kynan Lawlor, Belinda Phipson, Jovana Maksimovic, Lorna Hale, Sean Wilson, Catherine Quinlan, Gladys Ho, Katherine Holman and 8 more

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

Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 117 papers.

0numbers the graph read from it
0cells of the map it votes in
117citing papers in PubMed
8.7field-weighted citation impact, top 1% 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

117 citing papers in PubMed, 195 citations in OpenAlex.

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  15. Compound Heterozygous Variants in theDiagnostics (Basel, Switzerland) · 2024
    Article
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57 more citing papers are in PubMed but not listed here.

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

18 authors at 5 institutions in 1 country.

Thomas A ForbesKidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia; Department of Nephrology, Royal Children's Hospital, Parkville, VIC 3052, Australia.
Sara E HowdenKidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
Kynan LawlorKidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Belinda PhipsonKidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Bioinformatics Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Jovana MaksimovicBioinformatics Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Lorna HaleKidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
Sean WilsonKidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Catherine QuinlanKidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia; Department of Nephrology, Royal Children's Hospital, Parkville, VIC 3052, Australia.
Gladys HoDepartment of Molecular Genetics, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
Katherine HolmanDepartment of Molecular Genetics, Children's Hospital at Westmead, Sydney, NSW 2145, Australia.
Bruce BennettsDepartment of Molecular Genetics, Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, NSW 2145, Australia; Discipline of Paediatrics and Child Health and Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, NSW 2000, Australia.
Joanna CrawfordInstitute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia.
Peter TrnkaChild and Adolescent Renal Service, Lady Cilento Children's Hospital, Brisbane, QLD 4101, Australia; Faculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia.
Alicia OshlackKidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Bioinformatics Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
Chirag PatelGenetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
Andrew MallettFaculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia; Department of Renal Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
Cas SimonsInstitute for Molecular Bioscience, University of Queensland, St. Lucia, QLD 4072, Australia.
Melissa H LittleKidney Development, Disease, and Regeneration Group, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia. Electronic address: melissa.little@mcri.edu.au.
Murdoch Children's Research Institute · AUUniversity of Queensland · AUChildren's Hospital at Westmead · AURoyal Brisbane and Women's Hospital · AURoyal Children's Hospital · AU

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Despite the increasing diagnostic rate of genomic sequencing, the genetic basis of more than 50% of heritable kidney disease remains unresolved. Kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of individuals affected by inherited renal disease represent a potential, but unvalidated, platform for the functional validation of novel gene variants and investigation of underlying pathogenetic mechanisms. In this study, trio whole-exome sequencing of a prospectively identified nephronophthisis (NPHP) proband and her parents identified compound-heterozygous variants in IFT140, a gene previously associated with NPHP-related ciliopathies. IFT140 plays a key role in retrograde intraflagellar transport, but the precise downstream cellular mechanisms responsible for disease presentation remain unknown. A one-step reprogramming and gene-editing protocol was used to derive both uncorrected proband iPSCs and isogenic gene-corrected iPSCs, which were differentiated to kidney organoids. Proband organoid tubules demonstrated shortened, club-shaped primary cilia, whereas gene correction rescued this phenotype. Differential expression analysis of epithelial cells isolated from organoids suggested downregulation of genes associated with apicobasal polarity, cell-cell junctions, and dynein motor assembly in proband epithelial cells. Matrigel cyst cultures confirmed a polarization defect in proband versus gene-corrected renal epithelium. As such, this study represents a "proof of concept" for using proband-derived iPSCs to model renal disease and illustrates dysfunctional cellular pathways beyond the primary cilium in the setting of IFT140 mutations, which are established for other NPHP genotypes.

Indexed as

Amino Acid SequenceBase SequenceCarrier ProteinsCells, CulturedCellular ReprogrammingCerebellar AtaxiaCiliaEpithelial CellsExome SequencingFemaleFibroblastsFlagellaGene EditingGene Expression ProfilingHeterozygoteHumansCarrier ProteinsIFT140 protein, humanRNA, MessengerciliaCRISPR/Cas9functional genomicsgene correctionIFT140induced pluripotent stem cellskidney organoidnephronophthisis

Identifiers

PMID29706353
PMCPMC5986969
OpenAlexW2802030535

What OpenQuestion holds

Textmetadata
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.