Phenotypic variations between affected siblings with ataxia-telangiectasia: ataxia-telangiectasia in Japan

Morio, Tomohiro; Takahashi, Naomi; Watanabe, Fumiaki; Honda, Fumiko; Satō, Masaki; Takagi, Motoki; Imadome, Ken Ichi; Miyawaki, Toshio; Delia, Domenico; Nakamura, Kotoka; Gatti, Richard A.; Mizutani, Shuki

doi:10.1007/s12185-009-0408-0

Cited by 34 publications

(29 citation statements)

References 38 publications

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“…Thus, future studies are needed to determine whether persistent MHV68 replication is sufficient to induce lung pathology in ATM-deficient mice, which, unlike humans with A-T, do not spontaneously develop lung disease. While A-T patients display altered anti-EBV antibody responses suggestive of persistent viral replication (4,22,36), the status of EBV infection is poorly understood, and it is not known whether EBV contributes to the lung disease observed in A-T patients. The clinical finding that steroids, but not antibiotic treatment, suppress or even reverse lung deterioration in A-T patients (33,40) suggests that chronic immune stimulation that may be driven in part by virus infections does contribute to lung disease in A-T. Future studies are needed to define the relative contribution of chronic virus infections to the development and progression of lung disease in A-T patients.…”

Section: Implications For A-t and Other Ddr-linked Diseasesmentioning

confidence: 99%

“…Importantly, A-T patients seem to be selectively susceptible to severe herpesvirus infections. In one study, herpesviruses were the cause of 8 out of 11 severe viral infections observed in A-T patients (36). It is not known whether herpesvirus infection contributes to lung disease or cancer observed in the A-T population.…”

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confidence: 99%

“…Two known human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), are associated with cancer, including lymphomas (7). A-T patients have a skewed antibody response against EBV, with high titers of antibodies directed against lytic, but not latent, antigens of the virus (4,22,36). This antibody pattern implies uncontrolled persistent EBV replication.…”

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confidence: 99%

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Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

Kulinski

Leonardo

Mounce

et al. 2012

J Virol

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Gammaherpesviruses, such as Epstein-Barr virus (EBV), are ubiquitous cancer-associated pathogens that interact with DNA damage response, a tumor suppressor network. Chronic gammaherpesvirus infection and pathogenesis in a DNA damage response-insufficient host are poorly understood. Ataxia-telangiectasia (A-T) is associated with insufficiency of ataxia-telangiectasia mutated (ATM), a critical DNA damage response kinase. A-T patients display a pattern of anti-EBV antibodies suggestive of poorly controlled EBV replication; however, parameters of chronic EBV infection and pathogenesis in the A-T population remain unclear. Here we demonstrate that chronic gammaherpesvirus infection is poorly controlled in an animal model of A-T. Intriguingly, in spite of a global increase in T cell activation and numbers in wild-type (wt) and ATM-deficient mice in response to mouse gammaherpesvirus 68 (MHV68) infection, the generation of an MHV68-specific immune response was altered in the absence of ATM. Our finding that ATM expression is necessary for an optimal adaptive immune response against gammaherpesvirus unveils an important connection between DNA damage response and immune control of chronic gammaherpesvirus infection, a connection that is likely to impact viral pathogenesis in an ATM-insufficient host.

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Section: Implications For A-t and Other Ddr-linked Diseasesmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

Kulinski

Leonardo

Mounce

et al. 2012

J Virol

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“…ATMdeficient hosts, whether humans or mice, are selectively susceptible to severe chronic, but not acute, viral infections. Specifically, A-T patients display elevated EBV and HHV-6 loads, have prolonged and exacerbated primary varicella-zoster virus infection, and display more robust and persistent skin lesions associated with human papillomavirus (HPV) infection (11)(12)(13)(14)(15)(16)(17). These observations contradict the well-established proviral phenotypes in tissue culture systems, where ATM facilitates infection and replication of diverse herpesviruses and HPV.…”

Section: Discussionmentioning

confidence: 95%

“…Intriguingly, in contrast to the proviral activity of ATM manifested in tissue culture, A-T patients are selectively susceptible to severe herpesvirus infections, including frequent complications of primary varicella-zoster virus infection (11)(12)(13)(14)(15)(16)(17). Further, EBV (and human herpesvirus 6 [HHV-6], when present) loads are significantly elevated in A-T patients, and abnormal EBV-driven lymphoproliferation observed early in life has been suggested as a possible diagnostic trigger for A-T (12).…”

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confidence: 99%

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

Darrah

Kulinski

Mboko

et al. 2017

J Virol

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Manipulation of host cellular pathways is a strategy employed by gammaherpesviruses, including mouse gammaherpesvirus 68 (MHV68), in order to negotiate a chronic infection. Ataxia-telangiectasia mutated (ATM) plays a unique yet incompletely understood role in gammaherpesvirus infection, as it has both proviral and antiviral effects. Chronic gammaherpesvirus infection is poorly controlled in a host with global ATM insufficiency, whether the host is a mouse or a human. In contrast, ATM facilitates replication, reactivation, and latency establishment of several gammaherpesviruses in vitro, suggesting that ATM is proviral in the context of infected cell cultures. The proviral role of ATM is also evident in vivo, as myeloidspecific ATM expression facilitates MHV68 reactivation during the establishment of viral latency. In order to better understand the complex relationship between host ATM and gammaherpesvirus infection, we depleted ATM specifically in B cells, a cell type critical for chronic gammaherpesvirus infection. B cell-specific ATM deficiency attenuated the establishment of viral latency due to compromised differentiation of ATM-deficient B cells. Further, we found that during long-term infection, peritoneal B-1b, but not related B-1a, B cells display the highest frequency of gammaherpesvirus infection. While ATM expression did not affect gammaherpesvirus tropism for B-1 B cells, B cell-specific ATM expression was necessary to support viral reactivation from peritoneal cells during long-term infection. Thus, our study reveals a role of ATM as a host factor that promotes chronic gammaherpesvirus infection of B cells.IMPORTANCE Gammaherpesviruses infect a majority of the human population and are associated with cancer, including B cell lymphomas. ATM is a unique host kinase that has both proviral and antiviral roles in the context of gammaherpesvirus infection. Further, there is insufficient understanding of the interplay of these roles in vivo during chronic infection. In this study, we show that ATM expression by splenic B cells is required for efficient establishment of gammaherpesvirus latency. We also show that ATM expression by peritoneal B cells is required to facilitate viral reactivation during long-term infection. Thus, our study defines a proviral role of B cellspecific ATM expression during chronic gammaherpesvirus infection.KEYWORDS ATM, gammaherpesvirus, B cell, T cell response, reactivation, chronic infection A taxia-telangiectasia (A-T) mutated (ATM) kinase is a multifunctional kinase, insufficiency of which in humans manifests as A-T (1, 2). The function of ATM was originally defined in the context of response to double-stranded DNA breaks. However,

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Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia

Nakamura

Tunuguntla

et al. 2011

Hum. Mutat.

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A recent challenge for investigators studying the progressive neurological disease ataxia-telangiectasia (A-T) is to identify mutations whose effects might be alleviated by mutation-targeted therapies. We studied ATM mutations in eight families of Japanese A-T patients (JPAT) and were able to identify all 16 mutations. The probands were compound heterozygotes in seven families, and one (JPAT2) was homozygous for a frameshift mutation. All mutations - four frameshift, two nonsense, four large genomic deletions, and six affecting splicing - were novel except for c.748C>T found in family JPAT6 and c.2639−384A>G found in family JPAT11/12. Using an established lymphoblastoid cell line (LCL) of patient JPAT11, ATM protein was restored to levels approaching wildtype by exposure to an antisense morpholino oligonucleotide designed to correct a pseudoexon splicing mutation. In addition, in an LCL from patient JPAT8/9, a heterozygous carrier of a nonsense mutation, ATM levels could also be partially restored by exposure to readthrough compounds (RTC): an aminoglycoside, G418, and a novel small molecule identified in our laboratory, RTC13. Taken together, our results suggest that screening and functional characterization of the various sorts of mutations affecting the ATM gene can lead to better identification of A-T patients who are most likely to benefit from rapidly developing mutation-targeted therapeutic technologies.

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Phenotypic variations between affected siblings with ataxia-telangiectasia: ataxia-telangiectasia in Japan

Cited by 34 publications

References 38 publications

Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

Functional characterization and targeted correction of ATM mutations identified in Japanese patients with ataxia-telangiectasia

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