Evidence map›Paper›PMID 39106866›Full record

ArticleAmerican journal of human genetics2024

Expanding the genetic and phenotypic landscape of replication factor C complex-related disorders: RFC4 deficiency is linked to a multisystemic disorder.

Marie Morimoto, Eunjin Ryu, Benjamin J Steger, Abhijit Dixit, Yoshihiko Saito, Juyeong Yoo, Amelie T van der Ven, Natalie Hauser, Peter J Steinbach, Kazumasa Oura and 33 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
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

3 citing papers in PubMed.

  1. Article
  2. Article
  3. 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

43 authors.

Marie MorimotoNational Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Eunjin RyuCenter for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea; Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Benjamin J StegerNational Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Abhijit DixitNottingham University Hospital, Nottingham, UK.
Yoshihiko SaitoDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Juyeong YooCenter for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea; Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Amelie T van der VenInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Natalie HauserInova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA.
Peter J SteinbachBioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Kazumasa OuraDivision of Neurology and Gerontology, Department of Internal Medicine, School of Medicine Iwate Medical University, Morioka, Japan.
Alden Y HuangInstitute for Precision Health, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Fanny KortümInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Shinsuke NinomiyaDepartment of Clinical Genetics, Kurashiki Central Hospital, Okayama, Japan.
Elisabeth A RosenthalDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Hannah K RobinsonExeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Katie GueganExeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Jonas DeneckeDepartment of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Sankarasubramoney H SubramonyDepartment of Neurology, University of Florida College of Medicine, Gainesville, FL, USA.
Callie J DiamonsteinInova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA.
Jie PingDivision of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Mark FennerNottingham University Hospital, Nottingham, UK.
Elsa V BaltonDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Sam StrohbehnDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Aimee AllworthDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Michael J BamshadBrotman Baty Institute for Precision Medicine, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
Mahi GandhiDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Katrina M DippleBrotman Baty Institute for Precision Medicine, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
Elizabeth E BlueDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA; University of Washington School of Public Health, Institute for Public Health Genetics, Seattle, WA, USA.
Gail P JarvikDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA; Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
University of Washington Center for Rare Disease Research
C Christopher LauNational Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Ingrid A HolmDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Monika Weisz-HubshmanDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Benjamin D SolomonInova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA.
Undiagnosed Diseases Network
Stanley F NelsonInstitute for Precision Health, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Ichizo NishinoDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
David R AdamsNational Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Sukhyun KangCenter for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea.
William A GahlNational Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Camilo ToroNational Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Kyungjae MyungCenter for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea; Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
May Christine V MalicdanNational Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: maychristine.malicdan@nih.gov.

Funding

University of Washington Mendelian Genomics Research Center (UW-MGRC)U01HG011744 · NHGRI · UNIVERSITY OF WASHINGTON · PI MICHAEL Joseph BAMSHAD, Evan Eichler · 2021 to 2026
$15.8M
Pacific Northwest Undiagnosed Diseases Network Clinical SiteU01NS134355 · NINDS · UNIVERSITY OF WASHINGTON · PI ELIZABETH ELOYCE BLUE, Katrina M Dipple · 2023 to 2026
$3.0M
UCLA clinical site for the investigation of undiagnosed disordersU01NS134356 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MARTINEZ-AGOSTO, JULIAN, NELSON, STANLEY F. · 2023 to 2023
$936k
NHGRI NIH HHS U01 HG011744NINDS NIH HHS U01 NS134355NINDS NIH HHS U01 NS134356
6 · The paper itself

Abstract

The precise regulation of DNA replication is vital for cellular division and genomic integrity. Central to this process is the replication factor C (RFC) complex, encompassing five subunits, which loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. While RFC1's role in cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is known, the contributions of RFC2-5 subunits on human Mendelian disorders is largely unexplored. Our research links bi-allelic variants in RFC4, encoding a core RFC complex subunit, to an undiagnosed disorder characterized by incoordination and muscle weakness, hearing impairment, and decreased body weight. We discovered across nine affected individuals rare, conserved, predicted pathogenic variants in RFC4, all likely to disrupt the C-terminal domain indispensable for RFC complex formation. Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression. Our integrated approach of combining in silico, structural, cellular, and functional analyses establishes compelling evidence that bi-allelic loss-of-function RFC4 variants contribute to the pathogenesis of this multisystemic disorder. These insights broaden our understanding of the RFC complex and its role in human health and disease.

Indexed as

Replication Protein CAdultAllelesDNA ReplicationFemaleHeLa CellsHumansMaleMutationPhenotypeProliferating Cell Nuclear AntigenProliferating Cell Nuclear AntigenReplication Protein CDNA replicationgene discoveryMendelian disorderrare diseasereplication factor C complextranslational research

Identifiers

PMID39106866
PMCPMC11393705

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.