Oculocutaneous Telangiectasia Research Articles

Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations

Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immune defects and predisposition to malignancies. A-T is caused by biallelic inactivation of the ATM gene, in most cases by frameshift or nonsense mutations. More rarely, ATM missense mutations with unknown consequences on ATM function are found, making definitive diagnosis more challenging. In this study, a series of 15 missense mutations, including 11 not previously reported, were identified in 16 patients with clinical diagnosis of A-T belonging to 14 families and 1 patient with atypical clinical features. ATM function was evaluated in patient lymphoblastoid cell lines by measuring H2AX and KAP1 phosphorylation in response to ionizing radiation, confirming the A-T diagnosis for 16 cases. In accordance with previous studies, we showed that missense mutations associated with A-T often lead to ATM protein underexpression (15 out of 16 cases). In addition, we demonstrated that most missense mutations lead to an abnormal cytoplasmic localization of ATM, correlated with its decreased expression. This new finding highlights ATM mislocalization as a new mechanism of ATM dysfunction, which may lead to therapeutic strategies for missense mutation associated A-T.

Neuropathology in classical and variant ataxia‐telangiectasia

Ataxia-telangiectasia (A-T) is classically characterized by progressive neurodegeneration, oculocutaneous telangiectasia, immunodeficiency and elevated α-fetoprotein levels. Some patients, classified as variant A-T, exhibit a milder clinical course. In the latter patients extrapyramidal symptoms, instead of cerebellar ataxia, tend to be the dominating feature and other classical disease hallmarks, like telangiectasia, appear later or even may be absent. Some patients with variant disease have clinically pronounced anterior horn cell degeneration. Neuropathological studies of genetically proven A-T patients are lacking. The aims of our study were to describe the neuropathology of three A-T patients; in two of them the diagnosis was genetically confirmed. The neuropathological findings were compared with those of all known published autopsy findings in A-T patients up to now. Two classical A-T patients aged 19 and 22 and a 33-year-old patient with variant disease were autopsied. In line with previous reports, our patients had severe cerebellar atrophy, less pronounced degeneration of the dentate nucleus and inferior olive, degeneration of the posterior columns and neurogenic muscular atrophy. In addition, all three had anterior horn cell degeneration, which was most prominent at the lumbar level. Compared to the literature, the degenerative changes in the brain stem of the variant A-T patient were somewhat less than anticipated for his age. Degenerative changes in the cerebellum and spinal cord were comparable with those in the literature. Progeric changes were lacking. In conclusion, compared to classical A-T, the variant A-T patient showed essentially the same, only slightly milder neuropathological abnormalities, except for anterior horn degeneration.

New mutations in the ATM gene and clinical data of 25 AT patients

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, oculocutaneous telangiectasias, chromosomal instability, radiosensitivity, and cancer predisposition. The gene mutated in the patients, ATM, encodes a member of the phosphatidylinositol 3-kinase family proteins. The ATM protein has a key role in the cellular response to DNA damage. Truncating and splice site mutations in ATM have been found in most patients with the classical AT phenotype. Here we report of our extensive ATM mutation screening on 25 AT patients from 19 families of different ethnic origin. Previously unknown mutations were identified in six patients including a new homozygous missense mutation, c.8110T>C (p.Cys2704Arg), in a severely affected patient. Comprehensive clinical data are presented for all patients described here along with data on ATM function generated by analysis of cell lines established from a subset of the patients.

Inherited Hematologic and Oncologic Syndromes

Inherited Hematologic and Oncologic Syndromes

Heterotopic Purkinje cells in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is a heritable disorder of cerebellar ataxia and oculocutaneous telangiectasias caused by mutation of the ATM gene. The most prominent and consistent neuropathologic finding in the disorder is cerebellar cortical degeneration involving significant loss of granule and Purkinje cells. Several past autopsy studies of A-T patients have also noted large-bodied cells located within the molecular layer of the cerebellar cortex and, noting similarities in morphology between these cells and Purkinje cells, hypothesized that the cells were heterotopic Purkinje cells. This study aimed to test this hypothesis using an antibody that labels Purkinje cells, and also to investigate other cell types in the degenerating cerebellar cortex in A-T. Using the anti-calbindin D-28K antibody to label Purkinje cells in cerebellar tissue from five A-T patients and five age- and sex-matched controls, the study found calbindin-positive heterotopic Purkinje cells in the molecular layer occurring at a significantly higher rate in A-T patients than in controls (P = 0.012). Further immunohistochemistry with the anti-Iba-1 and anti-parvalbumin antibodies showed, respectively, an increase in microglial activity (P = 0.14) and stellate-cell density (P = 0.0048) in the cerebellar cortex of A-T patients versus controls. These data add to the as yet unresolved debate over the origin and significance of heterotopic Purkinje cells in A-T.

Efficacy of very-low-dose betamethasone on neurological symptoms in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is a non-curable neurodegenerative disorder, associated with progressive neurological dysfunction, oculocutaneous telangiectasia, immunodeficiency, predisposition to cancer and radiosensitivity. A recent study documented improvement in neurological symptoms after a short-term therapy with betamethasone in patients with A-T. Aim of this study was to evaluate the minimum therapeutically effective dosage of betamethasone on neurological symptoms of A-T. Six responsive patients with A-T, received two 20-day cycles of oral betamethasone at 0.01 and 0.03 mg/kg/day (10% and 30% of the previously used full dosage), each followed by a 20-day washout period. Clinical and laboratory evaluations were carried out at T0 and at the end of each cycle. Neurological assessment was performed through the Scale for the Assessment and Rating of Ataxia (SARA). The glucocorticoid-induced leucine zipper (GILZ) and glucocorticoid receptor (GR) RNA expression were evaluated before and during the trial through real-time PCR. SARA scores significantly improved in all patients at the dosage of 0.03 mg/kg/day. In particular, three patients exhibited an improvement in 5/8 variables and two patients of 7 and 8 variables, respectively. Furthermore, the clinical improvement was already evident after the lower dosage. The basal GILZ and GR RNA expression were significantly lower in patients than in controls. GILZ expression increased in all patients after the beginning of the therapy, whereas no correlation between GR and the response was found. Our data indicate that betamethasone is effective in A-T at a minimal dosage and that GILZ may be a useful biomarker of the clinical response. This study provides Class IIIA evidence that betamethasone at very low dosage is effective in improving neurological signs of patients affected with ataxia-telangiectasia.

Loss of ATM positively regulates the expression of hypoxia inducible factor 1 (HIF-1) through oxidative stress: Role in the physiopathology of the disease

Ataxia Telangiectasia (AT) is an autosomal recessive disorder characterized by a wide variety of progressive clinical symptoms. This includes neuronal degeneration, oculocutaneous telangiectasias, diabetes mellitus, immunodeficiency, increased risk of cancer and sensitivity to ionizing radiation. The gene mutated in this disease, ATM (Ataxia Telangiectasia Mutated), encodes a protein kinase involved in DNA double strand breaks signalling and repair. ATM deficient cells also display an increase in oxidative stress, by poorly characterized mechanism(s), which clearly contributes to the neurodegenerative aspect of the disease. Despite these advances, the occurrence of the vascular abnormalities, glucose intolerance and insulin resistance remains poorly understood. In different cellular models where ATM expression was disrupted, we demonstrated that the absence of ATM leads to an increased expression of both subunits of the transcription factor Hypoxia Inducible Factor 1 (HIF-1). We also observed enhanced trans-activating functions of HIF-1. HIF-1 is the central regulator of responses to hypoxia which induces the transcription of genes involved in angiogenesis (e.g VEGF -Vascular Endothelial Growth Factor) and cellular metabolism (e.g GLUT-1). Interestingly, we demonstrated that ATM disruption positively regulates both expression and function of the basal glucose transporter GLUT-1 as well as the proangiogenic factor, VEGF. In addition, our results suggest that the absence of ATM increases HIF-1 proteins biosynthesis, and this effect is dependant on the oxidative stress existing in ATM deficient cells. Our compelling results highlight a new link between ATM deficiency and the clinical features of the disease and provide a molecular link between ATM down-regulation and the increase in tumor angiogenesis observed in human breast cancers.

Hodgkin lymphoma in a young child contributing to a diagnosis of ataxia telangiectasia: review of the literature

Ataxia telangiectasia (A-T) is a rare genetic disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, chromosomal instability, and radiation sensitivity (Peterson et al. Lancet 283:1189–1193, 1964; Boder and Sedgwick Pediatrics 21:526–554, 1958; Taylor et al. Nature 258:427–429, 1975). Compared to the general population, patients with primary immunodeficiencies such as A-T have an increased rate of malignancy and an earlier age at presentation (Loeb et al. J Pediatr Hematol/Oncol 22:464–467, 2000; Taylor et al. Blood 87:423–438, 1996). We report the clinical, histopathologic, and molecular features of a 6-year-old child who presented with EBV-positive Hodgkin lymphoma (HL), which led to the diagnosis of ataxia telangiectasia. The diagnosis of HL at this unusually young age prompted further clinical, immunologic and cytogenetic evaluations, all of which supported a diagnosis of A-T. Because A-T patients are exquisitely sensitive to radiation, the patient was put on a modified chemotherapeutic regimen; however, 14 months later, he experienced a relapse and passed away by age 9. Classical HL is relatively rare among A-T patients, and this is the first documented case of an EBER-1 positive Hodgkin lymphoma in an ataxia telangiectasia patient. A review of the literature examining cases of HL in A-T is provided.

Cutaneous granulomatosis and combined immunodeficiency revealing Ataxia-Telangiectasia: a case report

Ataxia-telangiectasia (A-T) is a complex multisystem disorder characterized by progressive neurological impairment, variable immunodeficiency and oculo-cutaneous telangiectasia. A-T is a member of chromosomal breakage syndromes and it is caused by a mutation in the ataxia-telangiectasia mutated (ATM) gene. Because of a wide clinical heterogeneity, A-T is often difficult to diagnose in children.We report an unusual case of a 3-year-old boy affected by A-T who presented exclusively with extensive cutaneous granulomatosis and severe combined immunodeficiency, without neurological abnormalities, at the time of diagnosis. This case clearly emphasizes the variable presentation of A-T syndrome and highlights the difficulties in the early diagnosis of A-T.A-T should be considered in children with evidence of combined humoral and cellular immunodeficiency associated with unexplained skin granulomatous lesions, even in the absence of the classic features of this syndrome.

Malignancies and Outcome in Patients with Ataxia-Telangiectasia: Results From the French National Registry for Primary Immune Deficiencies.

Abstract 1101Poster Board I-123 BackgroundAtaxia-Telangiectasia (A-T) is rare inherited condition characterized by progressive neurological impairment, oculocutaneous telangiectasias, susceptibility to infections and predisposition to cancer. A-T is due to bi-allelic mutations in the ATM gene located on chromosome 11q23. ATM encodes a multifunction serine-threonine kinase involved detection and repair of DNA double-strand breaks, and regulation of cell-cycle check-points and apoptosis. A-T patients present an increased susceptibility to antimitotic chemotherapy and radiation.. Cancer is a major contributor to morbidity and mortality in A-T and ATM mutation analysis suggests a correlation between the presence of bi-allelic loss-of–function mutations and earlier onset of cancer, mainly hematological malignancies (R. Micol et al., manuscript submitted). Here we analyze the prevalence, histological subtype and outcome in A-T patients presenting with malignancies. MethodsTwo-hundred and fifty A-T patients born between 1954 and 2005 and included in the registry held by the French National Reference Center for Primary Immune Deficiencies (CEREDIH, manuscript submitted) were retrospectively analyzed. Clinical and histological data was extracted from the CEREDIH database. ResultsFifty-five patients (22% of the entire A-T cohort) presented with malignancies. Mean age at diagnosis of malignancy was 14.4 years (SD 9.8). Forty-nine patients (89%) presented with hematological malignancies and 6 (10.9%) with adenocarcinoma (3 mammary gland, 2 gastric, 1 thyroid). Hematological malignancies occurred earlier than carcinomas (mean 11.8 vs. 33.7 years respectively, p<001). High-grade Non-hodgkin lymphoma (NHL) was the most frequent hematological malignancy (31 patients, 56.3%) followed by Hodgkin's lymphoma (HL, 9 cases, 16.3%), acute lymphoblastic leukemia (ALL, 7 cases, 12,7%) and T-cell prolymphocytic leukaemia (T-PLL, 2 cases, 3.6%). Among NHL, 20 were of B-cell phenotype, including 4 cases of Burkitt's lymphoma. Three NHL were of T-cell phenotype and in 8 cases the phenotype was not available. Information on tumor staging was available for 18 NHL. Seventeen NHL were disseminated (Ann Arbor stage III/IV). Extranodal involvement was present in 14 NHL, absent in one case and unknown in 16. Six NHL (all B-cell) were EBV(+), 2 EBV(-) and in 23 cases the information was missing. Thirteen out of 14 NHL patients for whom treatment information was available received chemotherapy. Information on dosage was available for 11 patients. Five of them received a reduced dose. Three patients with ALL received chemotherapy including 1 who also received radiotherapy as part of conditioning for allogeneic HSCT. Of the 3 patients with carcinoma for whom information was available, 1 received chemotherapy only, one radiotherapy only and one both. Toxicity was recorded for 8 NHL patients (no toxicity in 2, hematological in 2, other in 4). Treatment response was recorded in 9 NHL patients (CR in 3, PR in 3 and no response in 3). Cause of death was recorded in 10 NHL patients: 7 patients died from tumor progression, 1 from infection and 2 from other causes. Mean survival after diagnosis of malignancy was 1.3 years for all histological subtypes. Comparison according to type of response to treatment showed that patients undergoing a major response had a longer survival than patients with minor or no response (mean survival 4.14 years for the former vs. 0.28 years for the latter, p<0.05). DiscussionMalignancy is a major contributor to morbidity and mortality in A-T, occurring in 22% of the present cohort. Hematological malignancies, mainly high grade B-cell NHL, are the most frequent cancers observed (56.3% of the observed malignancies and 12.4% of the patients in the cohort). EBV is associated with a noticeable proportion of high grade B-cell lymphomas, implying a possible contribution of the underlying immune deficiency in the pathogenesis of NHL during A-T. Tolerance to treatment including radiotherapy is variable. Despite poor overall survival, several patients underwent prolonged remissions and experienced improved survival. These results underscore the need to treat A-T patients with malignancies providing proper supportive care, including prevention and treatment of infections and mucositis. Further analysis of ATM mutations is required to determine if tolerance and response to treatment is correlated with the genotype. DisclosuresNo relevant conflicts of interest to declare.

Premature aging syndrome in ataxia telangiectasia patients

Ataxia telangiectasia (AT) is a genetic disorder caused by the mutation of the atm gene. It is characterized by progressive neurological abnormalities in combination with oculocutaneous telangiectasias, immunodeficiency, and increased frequency of malignancy. Cells of AT patients display increased radiosensitivity and premature aging markers, including shortened telomer length beginning at birth and limited proliferation potential. We studied radiosensitivity (at a dose 2 Gy) and the manifestation of premature aging markers in cultured skin fibroblasts derived from two unrelated AT patients and their heterozygous parents. We have shown that all the markers studied, i.e., HP1-γ, histone H2AX phosphorylated for serine-139 (γ-H2AX) and foci of 53BP1 protein, indicate the premature aging of the cells of both patients and their blood relatives. However, cells of heterozygous carriers express premature aging to a lesser extent. A study of the repair process (the amount of γ-H2AX and the number of cells with 53BP1 foci in their nuclei) after X-ray irradiation showed that patients’ cells only halfway completed repairs, even 24 h after irradiation, while the healthy donor cells completed repairs in 24 h. In cells from atm heterozygous donors, DNA repair was also slower. Heterozygous cells also differ reliably from healthy donor cells. Only amounts of p21Waf1/Cip1 protein, an inhibitor of cyclin-dependent kinases, in heterozygous cells do not differ from normal cells. However, the patients’ cells differ significantly. It was found that the mutation of the atm gene was related to the suppression of the reparation of DNA double-strand breaks (DSBs), which is in good agreement with increased radiosensitivity and premature aging in AT families at the cellular level.

Ataxia–telangiectasia patients presenting with hyper-IgM syndrome

Ataxia–telangiectasia (A–T) is characterised by progressive neurological abnormalities, oculocutaneous telangiectasias and immunodeficiency (decreased serum IgG subclass and/or IgA levels and lymphopenia). However, 10% of A–T patients present with decreased serum...

Inmunodeficiencia con ataxia telangiectasia. Reporte de un caso

Ataxia telangiectasia (AT) is a multisystemic complex syndrome that is typically transmitted in an autosomal recessive mode of inheritance and it is included among chromosomal breakage syndromes. The mutations on Ataxia-telangiectasia mutated (ATM) gen are the cause of AT disease. The risk to recurrent infection, with variable severity, is observed in 70 percent of these patients and it is attributed to their immunodeficiency. AT is a very rare disorder included in the Primary Immunodeficiency Syndromes. It occurs at a frequency of 1 case per 40 to 100,000 births worldwide with an estimated frequency of carriers of 1.4–2%. We present a case of a ten year- old male who had a past personal history of truncal and walking ataxia, generalized muscular hypotonia, and dysarthria beginning at age two. He also developed hyper and hypopigmentation in the skin and mucosa. At the age of three, an oculo-cutaneous telangiectasia appeared and nystagmus was found when he was six years and ten months old. On the other hand, he also began to suffer frequent episodes of infections of the upper and the lower respiratory tracts including: purulent rhinitis, maxilar sinusitis and bronchopneumonias as well as giardhiasis. Immunologic studies at the age of two revealed a decrease of the seric concentrations of IgG, IgA, high IgM values; low levels of IgE and high levels of alpha-fetoprotein. At seven, the MRI showed cerebellar atrophy. The amount of CD2+ CD8+ T lymphocytes was diminished. The patient was treated with gammaglobulin, balanced diet and vitamin therapy with satisfactory evolution in spite of the reserved prognosis for this syndrome that is characterized by a progressive neurodegeneration.

Uncommon Associations with Ataxia-Telangiectasia: Vitiligo and Optic Disc Drusen

Ataxia-telangiectasia (A–T) is an autosomal recesssive condition presented by progressive cerebellar ataxia, oculocutaneous telangiectasia, humoral and cellular immunodeficiencies and a predisposition to malignancy. We report on a 13 years old male patient with the diagnosis of A-T associated with uncommon clinical features; optic disc drusen and vitiligo. To our knowledge, this is the first report of A-T associated with these findings.

Prominent Oromandibular Dystonia and Pharyngeal Telangiectasia in Atypical Ataxia Telangiectasia

Ataxia telangiectasia (A-T) typically presents with early-onset progressive cerebellar ataxia, oculomotor apraxia and later, oculo-cutaneous telangiectasia. Extrapyramidal symptoms, apart from chorea, are rare. In this paper, we report a case of A-T with an atypically mild and slowly progressive disease course. Although by history there was mild gait clumsiness in early childhood, the leading problem was that of dystonia with onset at age 15, in the absence of gross gait imbalance or ocular motor apraxia. Dystonia was generalized and with prominent oromandibular involvement. Unusually, a leash of telangiectasia was present on the posterior pharyngeal wall, while other features frequently associated with A-T were absent.

ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia and oculocutaneous telangiectasias. Patients with A-T also have high incidences of type 2 diabetes mellitus. The gene mutated in this disease, ATM (A-T, mutated), encodes a protein kinase. Previous studies have demonstrated that cytoplasmic ATM is an insulin-responsive protein and a major upstream activator of Akt following insulin treatment. To further investigate the function of ATM in insulin signal transduction, insulin resistance was induced in rats by feeding them a high-fat diet. Muscle tissue of rats with insulin resistance had both dramatically reduced ATM levels and substantially decreased Akt phosphorylation at Ser473 in comparison to that of regular chow-fed controls. The decreased ATM expression suggests that ATM is involved in the development of insulin resistance through down-regulation of Akt activity. The role of ATM in activation of Akt was further confirmed in mouse embryonic fibroblast (MEF) A29 (ATM+/+) and A38 (ATM−/−) cells. In addition, insulin-mediated Akt phosphorylation in mouse L6 muscle cells was greatly reduced by KU-55933, a specific inhibitor of ATM. A 2-deoxyglucose incorporation assay showed that this inhibitor also caused a significant reduction in insulin-mediated glucose uptake in L6 cells. An immunofluorescence experiment demonstrated that in L6 cells transfected with wild-type (WT) ATM, insulin caused a dramatic increase of the cell surface glucose transporter 4 (GLUT4), while in cells transfected with kinase-dead (KD) ATM, translocation of GLUT4 to the cell surface in response to insulin was markedly inhibited.

Ataxia-Telangiectasia in Iran: Clinical and Laboratory Features of 104 Patients

Ataxia-telangiectasia is a multisystem disorder characterized by progressive neurologic impairment, variable immunodeficiency, impaired organ maturation, x-ray hypersensitivity, oculocutaneous telangiectasia, and a predisposition to malignancy. To evaluate clinical and immunologic features of Iranian patients with ataxia-telangiectasia, the records of 104 patients with ataxia-telangiectasia (54 male, 50 female) with the age range of 1.6-23.5 years were reviewed. The Iranian Primary Immunodeficiency Registry was used as the data source. Progressive ataxia was seen in all the patients. Other symptoms were eye movement disorders (n = 84), slurred speech (n = 70), mental retardation (n = 10), and ocular (n = 87) and cutaneous (n = 73) telangiectasia. Three patients developed leukemia and lymphoma, and 17 patients had family history of malignancy. Positive correlation was seen between clinical immunologic symptoms and immunoglobulin deficiencies (P = 0.004). The predominant infections were sinopulmonary and acute and recurrent infections (78 cases). Infections included pneumonia (56 patients), otitis media (34 patients), and sinusitis (50 patients). Average serum alpha-fetoprotein level was 149 +/- 137 ng/dL. The incidence of ataxia-telangiectasia in Iran is high, possibly due to familial marriages. Treatment should be focused on supportive management to prolong survival.

Lung disease in ataxia‐telangiectasia

Ataxia-telangiectasia (AT) is a multi-systemic disease caused by mutational inactivation of the ATM gene. We report a retrospective study of lung disease in 15 patients. A diagnosis of AT was made if the patient met the following criteria: neurological features and at least one the following: oculo-cutaneous telangiectasia, elevated serum alpha-feto-protein level. Recurrent sino-pulmonary infections were usually present in 11 of the cases and occurred during the first 2 years of life. Other lung injuries noted were bronchiectasis, obstruction and restriction of the airways, fibrosis, pneumothorax and haemoptysis. Eleven children had immunodeficiencies. Recurrent sino-pulmonary manifestations precede neurological complications, but the severity of neuro-degeneration and pulmonary disease were not correlated. Pulmonary status was a prognosis factor. Immunodeficiency was the main, but not the only, aetiology for lung disease in AT. There is little dispute over the role of ATM in lung and respiratory epithelium. To reduce the morbidity associated with AT, there needs to be greater awareness of respiratory complications. Early management and monitoring lung function is necessary to minimize lung damage.

Anti-Oxidant NAC Prevents Hypersensitivity, Immunodeficiency and Lymphomagenesis in Atm−/− Mice.

Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterized by immunodeficiency, progressive cerebellar ataxia, oculocutaneous telangiectasia, defective spermatogenesis, premature aging and high incidence of lymphoma. A-T is caused by the mutational inactivation of the “ataxia telangiectasia mutated” (ATM) gene. Ataxia telangiectasia mutated (ATM) plays a pivotal role in maintenance of genomic stability.Both A-T patients and Atm−/− mice show humeral and cellular immune defects, including thymic hypoplasia, low number of T-cells and deficiencies of Ig levels. It was originally believed that ATM was not essential for V(D)J recombination in T and B cells, a process which is mediated largely by the nonhomologous end-joining (NHEJ) pathway of DNA repair. However, several studies have revealed that ATM contributes to the prevention of interchromosomal translocations arising from aberrant V(D)J recombination. Thus, it remains unclear how ATM contributes to development of lymphocytes and prevention of lymphoma. It has been shown that deficient ATM function leads to abnormal reactive oxygen species (ROS) control. Several papers reported evidences for increased oxidative stress in tissues from A-T patients or Atm−/− mice, although the mechanism by which ATM regulates ROS level is unclear. Further, abnormalities in the levels and function of antioxidant systems in ATM-deficient cells have been reported. It has been assumed that increased ROS or abnormal response to ROS may contributes to neurodegenerative diseases and premature aging observed in A-T patients. We previously reported a critical role for ATM in stem cell self-renewal due to the effects of this kinase on the regulation of ROS during hematopoiesis. Treatment with the anti-oxidative agent N-acetyl-L-cystine (NAC) prevented the bone marrow failure observed in Atm−/− mice. It was reported that antioxidant prevented tumor development in p53−/− mice. Thus, appropriate ROS control is critical for clinical and cellular phenotypes of tumor-prone disorders.Here we show that a primary cause of immunodeficiency and lymphomagenesis in Atm−/− mice is the elevation of reactive oxygen species (ROS) present in these mutants. Reduction of ROS by NAC prevented the emergence of the senescent phenotype in mouse embryonic fibroblasts and hypersensitivity to total body irradiation in Atm−/− mice. The impairment of immunoglobulin class switch recombination (CSR) seen in Atm−/− mice was also mitigated by NAC, indicating that ROS elevation inhibits physiological DSBs rejoining in vivo. Significantly, in vivo treatment of Atm−/− mice with NAC restored normal T cell development, inhibited aberrant V(D)J recombination, and prevented thymic lymphomagenesis. We conclude that ATM-mediated ROS regulation is essential for the maintenance of genomic stability that prevents immunodeficiency and tumorigenesis. These findings may contribute to effective treatment of A-T patients for prevention of symptoms.

Ataxie–télangiectasie : de la clinique à la physiopathologie

Ataxia-telangiectasia (AT) is an autosomal recessive inherited disease caused by mutational inactivation of the ATM gene. It is a multisystemic disease, characterized by progressive neurological dysfunction, especially in the cerebellum, oculo-cutaneous telangiectasia, immunodeficiency, recurrent sino-pulmonary infections and high incidence of neoplasms. The responsible gene, ATM, encodes a large protein that belongs to a family of protein kinases with a phosphatidylinositol 3-kinase (Pi3K) domain. ATM is a key regulator of cell cycle checkpoints that causes DNA repair or apoptosis. Several studies report ATM function in target cells (such as neurons, fibroblast, endothelium, germ cells, lymphocytes). The pleiotropic phenotypes of AT reflect the multifaceted activities of ATM protein. In nucleus (lymphocytes, fibroblasts, germ cells) ATM is involved in regulation of cell-cycle checkpoints; in cytoplasm ATM regulates redox state (neurons).