Expanding the genetic and phenotypic landscape of replication factor C complex-related disorders: RFC4 deficiency is linked to a multisystemic disorder,American Journal of Human Genetics

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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
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2024-08-05 , DOI: 10.1016/j.ajhg.2024.07.008
Marie Morimoto ₁ , Eunjin Ryu ₂ , Benjamin J Steger ₁ , Abhijit Dixit ₃ , Yoshihiko Saito ₄ , Juyeong Yoo ₂ , Amelie T van der Ven ₅ , Natalie Hauser ₆ , Peter J Steinbach ₇ , Kazumasa Oura ₈ , Alden Y Huang ₉ , Fanny Kortüm ₅ , Shinsuke Ninomiya ₁₀ , Elisabeth A Rosenthal ₁₁ , Hannah K Robinson ₁₂ , Katie Guegan ₁₂ , Jonas Denecke ₁₃ , Sankarasubramoney H Subramony ₁₄ , Callie J Diamonstein ₆ , Jie Ping ₁₅ , Mark Fenner ₃ , Elsa V Balton ₁₁ , Sam Strohbehn ₁₁ , Aimee Allworth ₁₁ , Michael J Bamshad ₁₆ , Mahi Gandhi ₁₁ , Katrina M Dipple ₁₆ , Elizabeth E Blue ₁₇ , Gail P Jarvik ₁₈ , , C Christopher Lau ₁ , Ingrid A Holm ₁₉ , Monika Weisz-Hubshman ₂₀ , Benjamin D Solomon ₆ , , Stanley F Nelson ₂₁ , Ichizo Nishino ₄ , David R Adams ₂₂ , Sukhyun Kang ₂₃ , William A Gahl ₂₄ , Camilo Toro ₁ , Kyungjae Myung ₂₅ , May Christine V Malicdan ₂₄

Affiliation

National Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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.
Nottingham University Hospital, Nottingham, UK.
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Inova Translational Medicine Institute, Inova Health System, Falls Church, VA, USA.
Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Division of Neurology and Gerontology, Department of Internal Medicine, School of Medicine Iwate Medical University, Morioka, Japan.
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 Clinical Genetics, Kurashiki Central Hospital, Okayama, Japan.
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Neurology, University of Florida College of Medicine, Gainesville, FL, USA.
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Brotman Baty Institute for Precision Medicine, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
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.
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.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
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, 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.
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.
Center for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea.
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, USA.
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.

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.

中文翻译：

扩大复制因子 C 复合物相关疾病的遗传和表型景观：RFC4 缺陷与多系统疾病有关

DNA 复制的精确调节对于细胞分裂和基因组完整性至关重要。这个过程的核心是复制因子 C （RFC）复合物，它包含五个亚基，它将增殖的细胞核抗原加载到 DNA 上，以促进复制和修复蛋白质的募集，并增强 DNA 聚合酶的持续合成能力。虽然 RFC1 在小脑性共济失调、神经病变和前庭反射消失综合征（CANVAS）中的作用是已知的，但 RFC2-5 亚基对人类孟德尔疾病的贡献在很大程度上尚未得到探索。我们的研究将 RFC4 中的双等位基因变异（编码核心 RFC 复合物亚基）与一种以不协调和肌肉无力、听力障碍和体重减轻为特征的未确诊疾病联系起来。我们在 9 个受影响的个体中发现了 RFC4 中罕见、保守、可预测的致病性变异，所有这些变异都可能破坏 RFC 复合物形成所必需的 C 端结构域。对先前确定的与增殖细胞核抗原结合的 RFC 冷冻电镜结构的分析表明，这些变体会破坏 RFC4 内的相互作用和/或破坏 RFC 复合物的稳定性。使用 RFC4 缺陷型 HeLa 细胞和原代成纤维细胞的细胞研究表明，RFC4 蛋白减少，其他 RFC 复合物亚基的稳定性受损，并扰乱了 RFC 复合物的形成。此外，RFC4 变体的功能研究证实了 RFC 复合物形成减少，细胞周期研究表明 DNA 复制和细胞周期进程的扰动。我们结合计算机、结构、细胞和功能分析的综合方法建立了令人信服的证据，证明双等位基因功能丧失 RFC4 变体有助于这种多系统疾病的发病机制。这些见解拓宽了我们对 RFC 复合物及其在人类健康和疾病中的作用的理解。

更新日期：2024-08-05

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