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Expanding the genetic and phenotypic landscape of replication factor C complex-related disorders: RFC4 deficiency is linked to a multisystemic disorder.
Morimoto, Marie; Ryu, Eunjin; Steger, Benjamin J; Dixit, Abhijit; Saito, Yoshihiko; Yoo, Juyeong; van der Ven, Amelie T; Hauser, Natalie; Steinbach, Peter J; Oura, Kazumasa; Huang, Alden Y; Kortüm, Fanny; Ninomiya, Shinsuke; Rosenthal, Elisabeth A; Robinson, Hannah K; Guegan, Katie; Denecke, Jonas; Subramony, Sankarasubramoney H; Diamonstein, Callie J; Ping, Jie; Fenner, Mark; Balton, Elsa V; Strohbehn, Sam; Allworth, Aimee; Bamshad, Michael J; Gandhi, Mahi; Dipple, Katrina M; Blue, Elizabeth E; Jarvik, Gail P; Lau, C Christopher; Holm, Ingrid A; Weisz-Hubshman, Monika; Solomon, Benjamin D; Nelson, Stanley F; Nishino, Ichizo; Adams, David R; Kang, Sukhyun; Gahl, William A; Toro, Camilo; Myung, Kyungjae; Malicdan, May Christine V.
Afiliación
  • Morimoto M; National Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • Ryu E; Center 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.
  • Steger BJ; National Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • Dixit A; Nottingham University Hospital, Nottingham, UK.
  • Saito Y; Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • Yoo J; Center 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.
  • van der Ven AT; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Hauser N; Inova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA.
  • Steinbach PJ; Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Oura K; Division of Neurology and Gerontology, Department of Internal Medicine, School of Medicine Iwate Medical University, Morioka, Japan.
  • Huang AY; Institute 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.
  • Kortüm F; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Ninomiya S; Department of Clinical Genetics, Kurashiki Central Hospital, Okayama, Japan.
  • Rosenthal EA; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Robinson HK; Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
  • Guegan K; Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
  • Denecke J; Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Subramony SH; Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA.
  • Diamonstein CJ; Inova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA.
  • Ping J; Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Fenner M; Nottingham University Hospital, Nottingham, UK.
  • Balton EV; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Strohbehn S; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Allworth A; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Bamshad MJ; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
  • Gandhi M; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
  • Dipple KM; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
  • Blue EE; Division 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.
  • Jarvik GP; Division 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.
  • Lau CC; National Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • Holm IA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • Weisz-Hubshman M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Solomon BD; Inova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA.
  • Nelson SF; Institute 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, D
  • Nishino I; Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • Adams DR; National 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.
  • Kang S; Center for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea.
  • Gahl WA; National 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,
  • Toro C; National Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • Myung K; Center 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.
  • Malicdan MCV; National 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,
Am J Hum Genet ; 2024 Jul 31.
Article en En | MEDLINE | ID: mdl-39106866
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos