Ataxia‐telangiectasia: A review of clinical features and molecular pathology

Amirifar, Parisa; Ranjouri, Mohammad Reza; Yazdani, Reza; Abolhassani, Hassan; Aghamohammadi, Asghar

doi:10.1111/pai.13020

Cited by 144 publications

(131 citation statements)

References 133 publications

(275 reference statements)

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“…They also accumulate DNA double‐strand breaks and are highly susceptible to radiation‐induced cell death . ATM deficiency is typical for the progeroid syndrome ataxia‐telangiectasia, an inherited disease manifesting with neurodegeneration, premature aging, increased risk of malignancy, and accelerated cardiovascular disease . In RA T cells, ATM‐specific transcripts, ATM protein, and phosphorylated ATM are all downregulated (Figure ).…”

Section: Ra T Cells Bypass the G2/m Cell Cycle Checkpointmentioning

confidence: 99%

Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

115

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In rheumatoid arthritis (RA), breakdown of self‐tolerance and onset of clinical disease are separated in time and space, supporting a multi‐hit model in which emergence of autoreactive T cells is a pinnacle pathogenic event. Determining factors in T cell differentiation and survival include antigen recognition, but also the metabolic machinery that provides energy and biosynthetic molecules for cell building. Studies in patients with RA have yielded a disease‐specific metabolic signature, which enables naive CD4 T cells to differentiate into pro‐inflammatory helper T cells that are prone to invade into tissue and elicit inflammation through immunogenic cell death. A typifying property of RA CD4 T cells is the shunting of glucose away from glycolytic breakdown and mitochondrial processing toward the pentose phosphate pathway, favoring anabolic over catabolic reactions. Key defects have been localized to the mitochondria and the lysosome; including instability of mitochondrial DNA due to the lack of the DNA repair nuclease MRE11A and inefficient lysosomal tethering of AMPK due to deficiency of N‐myristoyltransferase 1 (NMT1). The molecular taxonomy of the metabolically reprogrammed RA T cells includes glycolytic enzymes (glucose‐6‐phosphate dehydrogenase, phosphofructokinase), DNA repair molecules (MRE11A, ATM), regulators of protein trafficking (NMT1), and the membrane adapter protein TSK5. As the mechanisms determining abnormal T cell behavior in RA are unraveled, opportunities will emerge to interject autoimmune T cells by targeting their metabolic checkpoints.

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Section: Ra T Cells Bypass the G2/m Cell Cycle Checkpointmentioning

confidence: 99%

Immunometabolism in the development of rheumatoid arthritis

Weyand

Goronzy

2020

Immunological Reviews

115

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“…A-T is an autosomal recessive disorder that has an estimated prevalence of 1:40,000 to 1:100,000 in the world population (Swift et al 1986). A-T patients are characterized by cerebellar ataxia, oculocutaneous telangiectasia (i.e., dilated blood vessels primarily in the ocular sclerae), and extreme sensitivity to ionizing radiation (IR) (Amirifar et al 2019). Primary immunodeficiency affecting T cell development and antibody isotype switch are also prevalent (Amirifar et al 2019).…”

Section: At Patients: Phenotypical and Molecular Characterizationmentioning

confidence: 99%

“…A-T patients are characterized by cerebellar ataxia, oculocutaneous telangiectasia (i.e., dilated blood vessels primarily in the ocular sclerae), and extreme sensitivity to ionizing radiation (IR) (Amirifar et al 2019). Primary immunodeficiency affecting T cell development and antibody isotype switch are also prevalent (Amirifar et al 2019). About 25% of A-T patients develop lymphoid malignancies, with a skew toward T cell leukemias in comparison to sporadic lymphomas (Boder 1985).…”

Section: At Patients: Phenotypical and Molecular Characterizationmentioning

confidence: 99%

ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

Menolfi

Zha

2019

GENOME INSTAB. DIS.

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Genomic integrity is critical for normal development, healthy aging and suppressing oncogenic transformation. The DNA damage response (DDR) is a complex network that is activated by DNA structural changes to preserve genome integrity. Situated at the apex of the mammalian DDR are three PI3-kinase-related protein kinases-ATM, DNA-PKcs and ATR. They are activated by different DNA lesions via direct binding to their unique sensor protein complexes (MRE11-RAD50-NBS1 for ATM, Ku70-Ku80/86 for DNA-PKcs and ATRIP-RPA for ATR) and phosphorylate a large number of partially overlapping substrates, including themselves and each other to promote DNA repair and regulate cell cycle checkpoints and tissue homeostasis. This review focuses on mouse models with deletion and point mutations of ATM, DNA-PKcs and ATR, and discusses how their activation mechanism and their kinase activity contribute to their unique, yet interactive roles in DNA repair in general and during tissue-specific development processes and how their deficiency leads to specific physiological and pathophysiological consequences.

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“…Ataxia-telangiectasia (A-T) is an autosomal recessive syndrome of primary immunodeficiency type (mutations of a specific A-T gene that encodes a protein kinase involved in DNA pathways) (4). A part from neurological and dermatological anomalies there is an increased risk of different malignancies (4). The clinical picture is heterogeneous depending on severity (4).…”

Section: Introductionmentioning

confidence: 99%

Neck telangiectasia: A case with a twist

Şandru¹,

Dumitrașcu²,

Valea³

et al. 2020

Ro Med J.

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Telangiectasia represents a sign on the skin underlining multiple conditions, characterised by red/purple/blue thin lines caused by dilatation of capillaries/arterioles/venules. Similar lesions may be detected during a surgical procedure at the surface of a solid organ. Pathological conditions associating the lesion are: dermatomyositis, scleroderma, lupus and the syndromes of ataxia-telangiectasia, respective hereditary hemorrhagic telangiectasia. We introduce a male case with anterior and lateral cervical enlargement with local skin changes of telangiectasia type. We introduce a male case with anterior and lateral cervical enlargement with local skin changes of telangiectasia type. The twist of the case is that, despite neck tegument red thin lines, the subject actually had a severe form of thyroid cancer. This is a case presentation. This is an 82-year old non-smoker male from non-endemic area admitted for rapidly enlargement of a tumor mass at neck in addition with local skin changes like telangiectasia and erythema as well as speech, eating and breathing intermittent disturbances. Thyroid function was normal. Thyroid ultrasound showed an enlargement of right lobe, of 3.7 by 4 by 7 cm (centimeter), mostly displayed by a macronodule with mix structure, of oval shape, with extension to isthmus, which is well shaped, of 5.7 by 4 by 5.2 cm. The data are highly suggestive for a thyroid cancer, thus the patient was further referred for total thyroidectomy. The changes of neck skin like telangiectasia and redness may exceptionally be caused by an aggressive thyroid cancer.

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Ataxia‐telangiectasia: A review of clinical features and molecular pathology

Cited by 144 publications

References 133 publications

Immunometabolism in the development of rheumatoid arthritis

Immunometabolism in the development of rheumatoid arthritis

ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

Neck telangiectasia: A case with a twist

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