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

复制(统计) 表型 遗传性疾病 遗传学 生物 病毒学 基因
作者
Marie Morimoto,Eunjin Ryu,Benjamin Steger,Abhijit Dixit,Yoshihiko Saito,Juyeong Yoo,Friedhelm Hildebrandt,Natalie Hauser,Peter Steinbach,Kazumasa Oura,Alden Huang,Fanny Kortüm,Shinsuke Ninomiya,Elisabeth A. Rosenthal,Hannah K. Robinson,Katie Guegan,Jonas Denecke,Sankarasubramoney H. Subramony,Callie Diamonstein,Jie Ping,Martin Fenner,Elsa Balton,Sam Strohbehn,Aimee Allworth,Michael J. Bamshad,Manish J. Gandhi,Katrina M. Dipple,Elizabeth Blue,Gail P. Jarvik,Chuen‐Yen Lau,Ingrid A. Holm,Monika Weisz-Hubshman,Benjamin D. Solomon,Stanley F. Nelson,Ichizo Nishino,David R. Adams,Sukhyun Kang,William A. Gahl,Camilo Toro,Kyungjae Myung,May Christine V. Malicdan
出处
期刊:American Journal of Human Genetics [Elsevier BV]
标识
DOI:10.1016/j.ajhg.2024.07.008
摘要

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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