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端粒功能障碍使 POT1 牵连进特发性肺纤维化患者中。

Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis.

机构信息

The Wistar Institute, Philadelphia, PA.

Department of Pulmonology, Interstitial Lung Disease Center of Excellence, St Antonius Hospital, Nieuwegein, Netherlands.

出版信息

J Exp Med. 2022 May 2;219(5). doi: 10.1084/jem.20211681. Epub 2022 Apr 14.

DOI:10.1084/jem.20211681
PMID:35420632
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9014792/
Abstract

Exonic sequencing identified a family with idiopathic pulmonary fibrosis (IPF) containing a previously unreported heterozygous mutation in POT1 p.(L259S). The family displays short telomeres and genetic anticipation. We found that POT1(L259S) is defective in binding the telomeric overhang, nuclear accumulation, negative regulation of telomerase, and lagging strand maintenance. Patient cells containing the mutation display telomere loss, lagging strand defects, telomere-induced DNA damage, and premature senescence with G1 arrest. Our data suggest POT1(L259S) is a pathogenic driver of IPF and provide insights into gene therapy options.

摘要

外显子测序鉴定了一个特发性肺纤维化（IPF）家系，该家系携带 POT1 基因 p.(L259S) 杂合突变，该突变为先前未报道过。该家系表现为端粒短和遗传早现。我们发现 POT1(L259S)在结合端粒突出、核内积累、端粒酶负调控和滞后链维持方面存在缺陷。携带该突变的患者细胞表现出端粒丢失、滞后链缺陷、端粒诱导的 DNA 损伤以及 G1 期阻滞的过早衰老。我们的数据表明 POT1(L259S)是 IPF 的致病性驱动因子，并为基因治疗提供了思路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/388a5d414ac1/JEM_20211681_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/8425b1459faa/JEM_20211681_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/5b700f4c6de6/JEM_20211681_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/a47f9023e0a8/JEM_20211681_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/1bc2393a67d2/JEM_20211681_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/9f2716e44ff2/JEM_20211681_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/50164caa0cde/JEM_20211681_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/7a0e8693ecfd/JEM_20211681_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/be375055f91b/JEM_20211681_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/388a5d414ac1/JEM_20211681_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/8425b1459faa/JEM_20211681_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/5b700f4c6de6/JEM_20211681_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/a47f9023e0a8/JEM_20211681_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/1bc2393a67d2/JEM_20211681_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/9f2716e44ff2/JEM_20211681_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/50164caa0cde/JEM_20211681_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/7a0e8693ecfd/JEM_20211681_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/be375055f91b/JEM_20211681_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/750b/9014792/388a5d414ac1/JEM_20211681_Fig9.jpg

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引用本文的文献

[1]
Active telomere elongation by a subclass of cancer-associated POT1 mutations.

Genes Dev. 2025-4-1

[2]
Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment.

Transfus Med Hemother. 2024-7-30

[3]
The evolving genetic landscape of telomere biology disorder dyskeratosis congenita.

EMBO Mol Med. 2024-10

[4]
Telomeres: Dysfunction, Maintenance, Aging and Cancer.

Aging Dis. 2023-11-29

[5]
Genetic Counseling and Family Screening Recommendations in Patients with Telomere Biology Disorders.

Curr Hematol Malig Rep. 2023-12

[6]
Possible molecular mechanisms underlying the development of atherosclerosis in cancer survivors.

Front Cardiovasc Med. 2023-6-2

[7]
A distal lung organoid model to study interstitial lung disease, viral infection and human lung development.

Nat Protoc. 2023-7

[8]
Familial Clonal Hematopoiesis in a Long Telomere Syndrome.

N Engl J Med. 2023-6-29

[9]
Present and future perspectives in early diagnosis and monitoring for progressive fibrosing interstitial lung diseases.

Front Med (Lausanne). 2023-2-15

[10]
Cellular and Molecular Mechanisms in Idiopathic Pulmonary Fibrosis.

Adv Respir Med. 2023-1-31

本文引用的文献

[1]
Distinct functions of POT1 proteins contribute to the regulation of telomerase recruitment to telomeres.

Nat Commun. 2021-9-17

[2]
Cancer-associated POT1 mutations lead to telomere elongation without induction of a DNA damage response.

EMBO J. 2021-6-15

[3]
Pol α-primase dependent nuclear localization of the mammalian CST complex.

Commun Biol. 2021-3-17

[4]
Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.

Nat Rev Mol Cell Biol. 2021-4

[5]
Role of POT1 in Human Cancer.

Cancers (Basel). 2020-9-24

[6]
A Germline Mutation in the Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer.

Cancers (Basel). 2020-6-1

[7]
Updated Evaluation of the Safety, Efficacy and Tolerability of Pirfenidone in the Treatment of Idiopathic Pulmonary Fibrosis.

Drug Healthc Patient Saf. 2020-5-7

[8]
Frequent Mutations of POT1 Distinguish Pulmonary Sarcomatoid Carcinoma From Other Lung Cancer Histologies.

Clin Lung Cancer. 2020-11

[9]
Human POT1 unfolds G-quadruplexes by conformational selection.

Nucleic Acids Res. 2020-5-21

[10]
mutation spectrum in tumour types commonly diagnosed among -associated hereditary cancer syndrome families.

J Med Genet. 2020-10

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