与 Chung-Jansen 综合征相关的 PHIP 变异会破坏复制叉的稳定性和基因组的完整性。

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-07-21 DOI:10.1101/mcs.a006212
Neysha Tirado-Class, Caitlin Hathaway, Wendy K Chung, Huzefa Dungrawala
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引用次数: 0

摘要

Chung-Jansen 综合征(CJS)是一种罕见的常染色体显性遗传疾病,以发育迟缓、智力残疾/认知障碍、行为障碍、肥胖和畸形为特征。CJS与PHIP(Pleckstrin-Homology Interacting Protein)的杂合子变异有关,该基因编码Cullin4-RING(CRL4)E3泛素连接酶复合物的几种底物受体之一。全长 PHIP 又称 DCAF14,最近被鉴定为一种复制应激反应蛋白。在此,我们报告了通过外显子测序在无关的 CJS 患者中发现的两个 PHIP 错义变体。变体p.D488V和p.E963G分别出现在DCAF14的不同功能元件--WD40重复域和pleckstrin同源结合区(PBR)。通过 DNA 纤维测定,我们发现表达这两种变体的细胞在复制胁迫条件下会表现出复制叉进展缺陷。此外,与野生型 DCAF14 不同的是,这两种变体在暴露于基因毒性应激后都无法完成 DNA 复制,这表明 DCAF14 在保护停滞的复制叉方面起着关键作用。因此,我们发现了与 CJS 变异相关的复制缺陷,并预测了与 CJS 综合征相关的复制基因组不稳定性。
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PHIP variants associated with Chung-Jansen syndrome disrupt replication fork stability and genome integrity.

Chung-Jansen syndrome (CJS) is a rare, autosomal dominant disorder characterized by developmental delay, intellectual disability/cognitive impairment, behavioral challenges, obesity, and dysmorphic features. CJS is associated with heterozygous variants in PHIP (Pleckstrin-Homology Interacting Protein), a gene that encodes one of several substrate receptors for Cullin4-RING (CRL4) E3 ubiquitin ligase complex. Full length PHIP, also called DCAF14, was recently identified to function as a replication stress response protein. Herein, we report the identification of two PHIP missense variants identified by exome sequencing in unrelated individuals with CJS. The variants p.D488V and p.E963G occur in different functional elements of DCAF14- WD40 repeat domain and pleckstrin homology-binding region (PBR), respectively. Using DNA fiber assays, we reveal that cells expressing either variant exhibit defective replication fork progression in conditions of replication stress. Furthermore, unlike wild type DCAF14, both variants fail to accomplish DNA replication after exposure to genotoxic stress indicating a critical role of DCAF14 in protecting stalled replication forks. Thus, we have identified replication defects associated with CJS variants and predict replication-associated genome instability with CJS syndrome.

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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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