C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

Richards, Anna; Maagdenberg, Arn M. J. M. van den; Jen, Joanna C.; Kavanagh, David; Bertram, Paula; Spitzer, Dirk; Liszewski, M. Kathryn; Barilla-LaBarca, Maria Louise; Terwindt, Gisela M.; Kasai, Yumi; McLellan, Michael D.; Grand, M. Gilbert; Vanmolkot, Kaate R J; Vries, Boukje de; Wan, Jijun; Kane, Michael J.; Mamsa, Hafsa; Schäfer, Ruth; Stam, Anine H.; Haan, Joost; Jong, Paulus T. V. M. de; Storimans, C. W. J. M.; Schooneveld, Mary J. van; Oosterhuis, J. A.; Gschwendter, Andreas; Dichgans, Martin; Kotschet, Katya; Hodgkinson, S.; Hardy, Todd A.; Delatycki, Martin B.; Hajj‐Ali, Rula A.; Kothari, Parul H.; Nelson, Stanley F.; Frants, Rune R.; Baloh, Robert W.; Ferrari, Michel D.; Atkinson, John P.

doi:10.1038/ng2082

Cited by 366 publications

(336 citation statements)

References 15 publications

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“…Removal of the aberrant cytoplasmic DNA by TREX1 probably mutes DNA damage signalling and checkpoint activation so that the inflammatory response cannot mount. Defective TREX1 is associated not only with Aicardi-Goutieres syndrome but also with ataxia telangiectasia-like symptoms (Lindahl et al 2009) and autosomal dominant retinal vasculopathy with cerebral leukodystrophy (Richards et al 2007), caused by C-terminal truncation and accompanied by loss of perinuclear localisation (see Table 3). This gives rise to the onset of stroke, dementia, loss of visual acuity and other pathologies prematurely in middle age, with death occurring within 10 years of disease onset (Richards et al 2007).…”

Section: Trex1 and Trex2mentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.

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Section: Trex1 and Trex2mentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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“…First, mutations in TREX1 can result in very disparate clinical phenotypes. Specifically, while TREX1 mutations that disable the exonuclease function in humans result in the neurologic features in AGS as described above, heterozygous C-terminal truncation mutations of TREX1, which do not involve the nuclease domain, result in a less severe disease with white matter involvement [54]. In contrast, other heterozygous TREX1 mutations do not result in neurologic disease, but instead cause the autoimmune disease systemic lupus erythromatosus (SLE) [55], and a dominant negative TREX1 mutation results in the related disorder familial chilblain lupus (FCL) [56,57].…”

Section: A New Model: Failure To Degrade Endogenous Dna Leads To Neurmentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

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“…Whilst it is entirely speculative to suggest that this may potentially reflect compromised ATR-pathway function in AGS, it would be relatively straight forward to investigate this. exonuclease activity but impact on Trex1 intra-cellular localisation [52]. Work on TREX1 is currently uncovering novel interacting proteins and should provide more information on the multifunctional nature of this enzyme [16].…”

Section: Some Outstanding Questionsmentioning

confidence: 99%

TREX1 DNA exonuclease deficiency, accumulation of single stranded DNA and complex human genetic disorders

O’Driscoll

2008

DNA Repair

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C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

Cited by 366 publications

References 15 publications

The role of DNA exonucleases in protecting genome stability and their impact on ageing

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

TREX1 DNA exonuclease deficiency, accumulation of single stranded DNA and complex human genetic disorders

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