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Quick Medical Genetics - Ataxia-telangiectasia
Lecture by Philip M. Boone, Ph.D about the genetic disease ataxia-telangiectasia for trainees and medical professionals.
Meschini R, Morucci E, Berni A, et al. Role of chromatin structure modulation by the histone deacetylase inhibitor trichostatin A on the radio-sensitivity of ataxia telangiectasia. Mutat Res. 2015; 777:52-9 [PubMed] Related Publications
At present, a lot is known about biochemical aspects of double strand breaks (DBS) repair but how chromatin structure affects this process and the sensitivity of DNA to DSB induction is still an unresolved question. Ataxia telangiectasia (A-T) patients are characterised by very high sensitivity to DSB-inducing agents such as ionising radiation. This radiosensitivity is revealed with an enhancement of chromosomal instability as a consequence of defective DNA repair for a small fraction of breaks located in the heterochromatin, where they are less accessible. Besides, recently it has been reported that Ataxia Telangiectasia Mutated (ATM) mediated signalling modifies chromatin structure. In order to study the impact of chromatin compaction on the chromosomal instability of A-T cells, the response to trichostatin-A, an histone deacetylase inhibitor, in normal and A-T lymphoblastoid cell lines was investigated testing its effect on chromosomal aberrations, cell cycle progression, DNA damage and repair after exposure to X-rays. The results suggest that the response to both trichostatin-A pre- and continuous treatments is independent of the presence of either functional or mutated ATM protein, as the reduction of chromosomal damage was found also in the wild-type cell line. The presence of trichostatin-A before exposure to X-rays could give rise to prompt DNA repair functioning on chromatin structure already in an open conformation. Differently, trichostatin-A post-treatment causing hyperacetylation of histone tails and reducing the heterochromatic DNA content might diminish the requirement for ATM and favour DSBs repair reducing chromosomal damage only in A-T cells. This fact could suggest that trichostatin-A post-treatment is favouring the slow component of DSB repair pathway, the one impaired in absence of a functionally ATM protein. Data obtained suggest a fundamental role of chromatin compaction on chromosomal instability in A-T cells.
Kuranova ML, Pleskach NM, Ledashcheva TA, et al. [Mosaic forms of ataxia-telangiectasia]. Tsitologiia. 2014; 56(8):619-29 [PubMed] Related Publications
Ataxia-telangiectasia (AT) is a severe hereditary autosomal recessive neurodegenerative disease associated with accelerated aging and caused by mutation in both alleles of atm gene. This gene encodes a key protein of cell response to DNA damage--an ATM protein kinase. Normally, upon formation of DNA double strand breaks ATM is autophosphorylated and its active form phospho-ATM (P-ATM) appears. Here we describe a mosaic form of AT in which cells of the same patient with normal atm gene demonstrated the accumulation of P-ATM in response to DNA double-strand breaks-inducing factors whereas in cells bearing a mutant form of atm P-ATM was not detected. The epigenetic markers such as histone deacetylases SIRT1 and SIRT6, and trimethylated forms of histone H3 - H3K9me3 and H3K27me3--were studied in the nuclei of primary fibroblasts derived from patients with different forms of AT and the increase of SIRT6 level was revealed.
Kim YJ, Ahn KS, Kim M, et al. Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer. Biochem Biophys Res Commun. 2014; 452(4):901-5 [PubMed] Related Publications
Ataxia telangiectasia (A-T) is a recessive autosomal disorder associated with pleiotropic phenotypes, including progressive cerebellar degeneration, gonad atrophy, and growth retardation. Even though A-T is known to be caused by the mutations in the Ataxia telangiectasia mutated (ATM) gene, the correlation between abnormal cellular physiology caused by ATM mutations and the multiple symptoms of A-T disease has not been clearly determined. None of the existing ATM mouse models properly reflects the extent to which neurological degeneration occurs in human. In an attempt to provide a large animal model for A-T, we produced gene-targeted pigs with mutations in the ATM gene by somatic cell nuclear transfer. The disrupted allele in the ATM gene of cloned piglets was confirmed via PCR and Southern blot analysis. The ATM gene-targeted pigs generated in the present study may provide an alternative to the current mouse model for the study of mechanisms underlying A-T disorder and for the development of new therapies.
Gilmore EC DNA repair abnormalities leading to ataxia: shared neurological phenotypes and risk factors. Neurogenetics. 2014; 15(4):217-28 [PubMed] Related Publications
Since identification of mutations in the ATM gene leading to ataxia-telangiectasia, enormous efforts have been devoted to discovering the roles this protein plays in DNA repair as well as other cellular functions. Even before the identification of ATM mutations, it was clear that other diseases with different genomic loci had very similar neurological symptoms. There has been significant progress in understanding why cancer and immunodeficiency occur in ataxia-telangiectasia even though many details remain to be determined, but the field is no closer to determining why the nervous system requires ATM and other DNA repair genes. Even though rodent disease models have similar DNA repair abnormalities as the human diseases, they have no consistent, robust neuropathological phenotype making it difficult to understand the neurological underpinnings of disease. Therefore, it may be useful to reassess the neurological and neuropathological characteristics of ataxia-telangiectasia in human patients to look for potential commonalities in DNA repair diseases that result in ataxia. In doing so, it is clear that ataxia-telangiectasia and similar diseases share neurological features other than merely ataxia, such as length-dependent motor and sensory neuropathies, and that the neuroanatomical localization for these symptoms is understood. Cells affected in ataxia-telangiectasia and similar diseases are some of the largest single nucleated cells in the body. In addition, a subset of these diseases also has extrapyramidal movements and oculomotor apraxia. These neurological and neuropathological similarities may indicate a common DNA repair related pathogenesis with very large cell size as a critical risk factor.
Ataxia-telangiectasia mutated (ATM) kinase, the mutation of which causes the autosomal recessive disease ataxia-telangiectasia, plays an essential role in the maintenance of genome stability. Extensive studies have revealed that activated ATM signals to a massive list of proteins to facilitate cell cycle checkpoints, DNA repair, and many other aspects of physiological responses in the event of DNA double-strand breaks. ATM also plays functional roles beyond the well-characterized DNA damage response (DDR). In this review article, we discuss the recent findings on the molecular mechanisms of ATM in DDR, the mitotic spindle checkpoint, as well as hyperactive ATM signaling in cancer invasion and metastasis.
Hasegawa S, Imai K, Yoshida K, et al. Whole-exome sequence analysis of ataxia telangiectasia-like phenotype. J Neurol Sci. 2014; 340(1-2):86-90 [PubMed] Related Publications
A number of diseases exhibit neurodegeneration with/without additional symptoms such as immunodeficiency, increased cancer risk, and microcephalus. Ataxia telangiectasia and Nijmegen breakage syndrome, for example, develop as a result of mutations in genes involved in the DNA damage response. However, such diseases can be difficult to diagnose as they are only rarely encountered by physicians. To overcome this challenge, nine patients with symptoms that resemble those of ataxia telangiectasia, including neurodegeneration, hypogammaglobulinemia, telangiectasia, and/or elevated serum α-fetoprotein, were subjected to whole-exome sequencing (WES) to identify the causative mutations. Molecular diagnosis was achieved in two patients: one displayed CD40 ligand (CD40LG) deficiency, while a second showed a homozygous SIL1 mutation, which has been linked to Marinesco-Sjögren syndrome (MSS). Typical features of CD40LG deficiency and MSS are distinct from the symptoms usually seen in ataxia telangiectasia. These dissociations between phenotype and genotype make it difficult to achieve molecular diagnosis of orphan diseases. Whole-exome sequencing analyses will assist in the molecular diagnosis of such cases and allow the identification of genotypes that would not be expected from the phenotype.
Sharma NK, Lebedeva M, Thomas T, et al. Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia. DNA Repair (Amst). 2014; 13:22-31 [PubMed] Related Publications
Ataxia Telangiectasia (A-T) is a progressive childhood disorder characterized most notably by cerebellar degeneration and predisposition to cancer. A-T is caused by mutations in the kinase ATM, a master regulator of the DNA double-strand break response. In addition to DNA-damage signaling defects, A-T cells display mitochondrial dysfunction that is thought to contribute to A-T pathogenesis. However, the molecular mechanism leading to mitochondrial dysfunction in A-T remains unclear. Here, we show that lack of ATM leads to reduced mitochondrial DNA (mtDNA) integrity and mitochondrial dysfunction, which are associated to defective mtDNA repair. While protein levels of mtDNA repair proteins are essentially normal, in the absence of ATM levels specifically of DNA ligase III (Lig3), the only DNA ligase working in mitochondria is reduced. The reduction of Lig3 is observed in different A-T patient cells, in brain and pre-B cells derived from ATM knockout mice as well as upon transient or stable knockdown of ATM. Furthermore, pharmacological inhibition of Lig3 in wild type cells phenocopies the mtDNA repair defects observed in A-T patient cells. As targeted deletion of LIG3 in the central nervous system causes debilitating ataxia in mice, reduced Lig3 protein levels and the consequent mtDNA repair defect may contribute to A-T neurodegeneration. A-T is thus the first disease characterized by diminished Lig3.
The symptoms of ataxia-telangiectasia (A-T) include a progressive neurodegeneration caused by ATM protein deficiency. We previously found that nuclear accumulation of histone deacetylase-4, HDAC4, contributes to this degeneration; we now report that increased trimethylation of histone H3 on Lys27 (H3K27me3) mediated by polycomb repressive complex 2 (PRC2) is also important in the A-T phenotype. Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability. Thus, PRC2 formation is elevated along with H3K27me3 in ATM deficiency. Chromatin immunoprecipitation and sequencing showed an increase in H3K27me3 'marks' and a dramatic shift in their location. The change of H3K27me3 chromatin-binding pattern is directly related to cell cycle reentry and cell death of ATM-deficient neurons. Lentiviral knockdown of EZH2 rescued Purkinje cell degeneration and behavioral abnormalities in Atm(-/-) mice, demonstrating that EZH2 hyperactivity is another key factor in A-T neurodegeneration.
Ataxia telangiectasia (AT) and ataxia oculomotor apraxia type 2 (AOA2) are autosomal recessive ataxias caused by mutations in genes involved in maintaining DNA integrity. Lifespan in AT is greatly shortened (20s-30s) due to increased susceptibility to malignancies (leukemia/lymphoma). Lifespan in AOA2 is uncertain. We describe a woman with variant AT with two novel mutations in ATM (IVS14+2T>G and 5825C>T, p.A1942V) who died at age 48 with pancreatic adenocarcinoma. Her mutations are associated with an unusually long life for AT and with a cancer rarely associated with that disease. We also describe two siblings with AOA2, heterozygous for two novel mutations in senataxin (3 bp deletion c.343-345 and 1398T>G, p.I466M) who have survived into their 70s, allowing us to characterize the longitudinal course of AOA2. In contrast to AT, we show that persons with AOA2 can experience a prolonged lifespan with considerable motor disability.
Ataxia telangiectasia (AT) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia-mutated gene (ATM). AT carriers with one mutant ATM allele are usually not severely affected although they carry an increased risk of developing cancer. There has not been an easy and reliable diagnostic method to identify AT carriers. Cell cycle checkpoint functions upon ionizing radiation (IR)-induced DNA damage and gene expression signatures were analyzed in the current study to test for differential responses in human lymphoblastoid cell lines with different ATM genotypes. While both dose- and time-dependent G1 and G2 checkpoint functions were highly attenuated in ATM-/- cell lines, these functions were preserved in ATM+/- cell lines equivalent to ATM+/+ cell lines. However, gene expression signatures at both baseline (consisting of 203 probes) and post-IR treatment (consisting of 126 probes) were able to distinguish ATM+/- cell lines from ATM+/+ and ATM-/- cell lines. Gene ontology (GO) and pathway analysis of the genes in the baseline signature indicate that ATM function-related categories, DNA metabolism, cell cycle, cell death control, and the p53 signaling pathway, were overrepresented. The same analyses of the genes in the IR-responsive signature revealed that biological categories including response to DNA damage stimulus, p53 signaling, and cell cycle pathways were overrepresented, which again confirmed involvement of ATM functions. The results indicate that AT carriers who have unaffected G1 and G2 checkpoint functions can be distinguished from normal individuals and AT patients by expression signatures of genes related to ATM functions.
Ataxia telangiectasia (AT) is a rare neurodegenerative disorder, inherited in an autosomal recessive manner. Total blood samples were collected from 20 patients with AT, 13 parents of patients, and 17 healthy volunteers. This study aimed at evaluating the frequency of chromosomal breaks in spontaneous cultures, induced by bleomycin and ionizing radiation, and further evaluated the rates of oxidative stress in AT patients and in their parents, compared to a control group. Three cell cultures were performed to each individual: the first culture did not receive induction to chromosomal instability, the second was exposed to bleomycin, and the last culture was exposed to ionizing radiation. To evaluate the rates of oxidative stress, the markers superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid (TBARS) were utilized. Significant differences were observed between the three kinds of culture treatments (spontaneous, bleomycin, and radiation induced) and the breaks and chromosomal aberrations in the different groups. The oxidative stress showed no significant differences between the markers. This study showed that techniques of chromosomal instability after the induction of ionizing radiation and bleomycin are efficient in the identification of syndrome patients, with the ionizing radiation being the most effective.
DNA double-strand breaks (DSBs) can lead to instability of the genome if not repaired correctly. The MRE11/RAD50/NBS1 (MRN) complex binds DSBs and initiates damage-induced signaling cascades via activation of the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia- and rad3-related (ATR) kinases. Mutations throughout MRE11 cause ataxia-telangiectasia-like disorder (ATLD) featuring cerebellar degeneration, and cancer-predisposition in certain kindreds. Here, we have examined the impact on DNA damage signaling of several disease-associated MRE11A alleles to gain greater understanding of the mechanisms underlying the diverse disease sequelae of ATLD. To this end, we have designed a system whereby endogenous wild-type Mre11a is conditionally deleted and disease-associated MRE11 mutants are stably expressed at physiologic levels. We find that mutations in the highly conserved N-terminal domain impact ATM signaling by perturbing both MRE11 interaction with NBS1 and MRE11 homodimerization. In contrast, an inherited allele in the MRE11 C-terminus maintains MRN interactions and ATM/ATR kinase activation. These findings reveal that ATLD patients have reduced ATM activation resulting from at least two distinct mechanisms: (i) N-terminal mutations destabilize MRN interactions, and (ii) mutation of the extreme C-terminus maintains interactions but leads to low levels of the complex. The N-terminal mutations were found in ATLD patients with childhood cancer; thus, our studies suggest a clinically relevant dichotomy in MRE11A alleles. More broadly, these studies underscore the importance of understanding specific effects of hypomorphic disease-associated mutations to achieve accurate prognosis and appropriate long-term medical surveillance.
Ataxia telangiectasia (A-T) is an autosomal recessive disease characterized mainly by progressive cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency. This disease is caused by mutations of the ataxia telangiectasia mutated (Atm) gene. More than 500 Atm mutations that are responsible for A-T have been identified so far. However, there have been very few A-T cases reported in China, and only two Chinese A-T patients have undergone Atm gene analysis. In order to systemically investigate A-T in China and map their Atm mutation spectrum, we recruited eight Chinese A-T patients from six unrelated families nationwide. Using direct sequencing of genomic DNA and the multiplex ligation-dependent probe amplification, we identified twelve pathogenic Atm mutations, including one missense, four nonsense, five frameshift, one splicing, and one large genomic deletion. All the Atm mutations we identified were novel, and no homozygous mutation and founder-effect mutation were found. These results suggest that Atm mutations in Chinese populations are diverse and distinct largely from those in other ethnic areas.
Lavin MF The appropriateness of the mouse model for ataxia-telangiectasia: neurological defects but no neurodegeneration. DNA Repair (Amst). 2013; 12(8):612-9 [PubMed] Related Publications
Patients with ataxia-telangiectasia (A-T) are characterised by genome instability, cancer predisposition and a progressive neurodegeneration. A number of model systems have been developed for A-T but none recapitulate all the phenotype. The majority of these models have been generated in mice. While Atm deficient mouse models exhibit much of the phenotype described in patients with A-T, the broad consensus is that they do not display the most debilitating aspect of A-T, i.e. neurodegeneration. Cerebellar atrophy is one of the neuronal characteristics of A-T patients due to defects in neuronal development and progressive loss of Purkinje and granule cells. This is not evident in Atm-deficient mutants but there are multiple reports on neurological abnormalities in these mice. The focus of this review is to evaluate the appropriateness of Atm mutant mouse models for A-T, particularly with reference to neurological abnormalities and how they might relate to neurodegeneration.
Loss of ATM kinase, a transducer of the DNA damage response and redox sensor, causes the neurodegenerative disorder ataxia-telangiectasia (A-T). While a great deal of progress has been made in elucidating the ATM-dependent DNA damage response (DDR) network, a key challenge remains in understanding the selective susceptibility of the nervous system to faulty DDR. Several factors appear implicated in the neurodegenerative phenotype in A-T, but which of them plays a crucial role remains unclear, especially since mouse models of A-T do not fully mirror the respective human syndrome. Therefore, a number of human neural stem cell (hNSC) systems have been developed to get an insight into the molecular mechanisms of neurodegeneration as consequence of ATM inactivation. Here we review the hNSC systems developed by us an others to model A-T.
Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features of A-T.
Claes K, Depuydt J, Taylor AM, et al. Variant ataxia telangiectasia: clinical and molecular findings and evaluation of radiosensitive phenotypes in a patient and relatives. Neuromolecular Med. 2013; 15(3):447-57 [PubMed] Related Publications
Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum α-fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient.
Bielorai B, Fisher T, Waldman D, et al. Acute lymphoblastic leukemia in early childhood as the presenting sign of ataxia-telangiectasia variant. Pediatr Hematol Oncol. 2013; 30(6):574-82 [PubMed] Related Publications
Ataxia-telangiectasia (A-T), an autosomal recessive disorder is characterized by progressive neurodegeneration, immunodeficiency, sensitivity to ionizing radiation, and predisposition to cancer, especially to lymphoid malignancies. A-T variant is characterized by a milder clinical phenotype and is caused by missense or leaky splice site mutations that produce residual ataxia telangiectasia mutated (ATM) kinase activity. Lymphoid malignancy can precede the diagnosis of A-T, particularly in young children with mild neurological symptoms. We studied a consanguineous family with four A-T variant patients, three of them developed T-ALL at a young age before the diagnosis of A-T was established. ATM mutation analysis detected two new missense mutations both within exon 12: c.1514T>C and c.1547T>C. All four patients are homozygous for the two mutations, while their parents are heterozygous for the mutations. ATM protein level was low in all patients and the response to the radiomimetic agent, neocarzinostatin, was reduced. Leukemic presentation in a young age in three members of consanguineous family led to the identification of a new missense mutation in the ATM gene. The diagnosis of A-T or A-T variant should be considered in children with neurological abnormalities who develop T-ALL at a young age.
In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell-cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients-children and adults alike-which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.
Palmeri S, Rufa A, Pucci B, et al. Clinical course of two Italian siblings with ataxia-telangiectasia-like disorder. Cerebellum. 2013; 12(4):596-9 [PubMed] Related Publications
Ataxia-telangiectasia-like disorder (ATLD) due to mutations in the MRE11 gene is a very rare autosomal recessive disease, described so far in only 20 patients. Little is known about the onset of the first symptoms or the clinical course of the disease. The present report contributes to the diagnosis of ATLD and its prognosis at onset. We report 30 years of clinical and ophthalmic observations and the results of quantitative magnetic resonance (MR), MR spectroscopy (proton magnetic resonance spectroscopic imaging) and neuropsychological assessment in the first Italian siblings identified with ATLD. Although the disease had early onset and the clinical picture was initially severe, suggesting ataxia-telangiectasia, neurological impairment, ocular motor apraxia and neuropsychological tests showed very slow deterioration in adult age. The patients developed eye and head motor strategies to compensate ocular motor apraxia. MR measurements and MR spectroscopy disclosed widespread neuronal and axonal involvement. ATLD should be considered in patients with ocular apraxia and ataxia in infancy. The long follow-up provided insights into clinical outcome, with functional neuroimaging studies shedding light on the pathogenetic mechanisms of this rare disease.
Jeddane L, Ailal F, Dubois-d'Enghien C, et al. Molecular defects in Moroccan patients with ataxia-telangiectasia. Neuromolecular Med. 2013; 15(2):288-94 [PubMed] Related Publications
Ataxia-telangiectasia (AT) is a rare autosomal recessive disease, affecting neurologic and immune system. Numerous mutations are described in the ATM gene in several populations. However, in Morocco, few data are available concerning this condition. Our main goal is to determine clinical, immunological, and molecular presentation of Moroccan patients with AT. We screened 27 patients, out of 22 unrelated families, for ATM gene mutations. All our patients showed ataxia, ocular telangiectasia, and immunodeficiency, as well as elevated serum alphafetoprotein levels. Mean age at diagnosis was 5.51 years, and consanguinity rate was 81.8 %. Mean age at onset was 2.02 years, and mean time to diagnosis was 3.68 years. We found 14 different mutations in 19 unrelated families, of which 7 were not reported. Our results showed that c.5644C>T mutation was the most common in our series. However, further studies are required to demonstrate a founder effects on ATM gene in Moroccan patients, who showed mutational heterogeneity otherwise. Our data indicate that direct sequencing of coding exons is sufficient for a high detection rate in ATM in Moroccan population.
Kuranova ML, Ledashcheva TA, Tulush EK, et al. [Diagnostics of ataxia-telangiectasia by the express-test found on the method of indirect immunofluorescence]. Tsitologiia. 2013; 55(8):560-5 [PubMed] Related Publications
Ataxia-telangiectasia (AT) is a hereditary severe neurodegenerative disease developing, when mutations take place in both alleles of the atm gene, which encodes the key protein of the cellular response to DNA damage (DDR)--ATM proteinkinase. In response to the occurrence of double-strand DNA breaks, the ATM proteinkinase pass the autophosphorylation, and its active form--the phospho-ATM (P-ATM) appears in cells. In the nuclei of cells having the atm gene, P-ATM is revealed, being absent in cells with mutated forms of this gene, by means of the application of the modified method of indirect immunofluorescence. This peculiarity may be applied in the clinic, in order to confirm the diagnosis of AT.
Rudenskaia GE, Kurkina MV, Zakharova EIu [Ataxia with oculomotor apraxia: clinical-genetic characteristics and DNA-diagnostic]. Zh Nevrol Psikhiatr Im S S Korsakova. 2012; 112(10):58-63 [PubMed] Related Publications
AOA are autosomal recessive ataxias with a common feature of oculomotor apraxia (OA) - inability to coordinate eye movements. The group includes AOA1 (APTX gene), relatively common AOA2 (SETX gene) and AOA3 (PIK 3R5 gene) described in 2012 in a Saudi family. OA is typical also for Louis-Bar ataxia-telangiectasia and its variants. А first Russian AOA2 case confirmed by DNA test is presented. The disease in a 25-year-old male started in 18 years, in 23 years he lost independent walking due to incoordination and weakness. OA produced few symptoms and was not recorded previously. Sensorimotor axonal polyneuropathy was confirmed by EMG. MRI showed cerebellar atrophy. Alpha-fetoprotein level was tenfold raised. A hereditary ataxia was considered from the disease onset, and a number of genetic tests were performed, but AOA2 was recognized only seven years later. On direct sequencing of SETX exons 6-8 a novel frame-shift mutation с.2623-2626 del 4 in heterozygous state was detected which is sufficient for AOA2 confirmation; the allelic mutation is in search. Recently a first Russian AOA1 case in a 15-year-old girl was also confirmed in our laboratory: compound-heterozygosity for two novel APTX mutations was detected. Evidently AOA are underestimated in clinical diagnostics while DNA testing permits genetic prophylaxis in families. OA should be purposefully searched for in children and young adults suspicious of autosomal recessive ataxias.
Recent development of next-generation DNA sequencing (NGS) techniques is changing the approach to search for mutations in human genetic diseases. We applied NGS to study an A-T patient in which one of the two expected mutations was not found after DHPLC, cDNA sequencing and MLPA screening. The 160-kb ATM genomic region was divided into 31 partially overlapping fragments of 4-6 kb and amplified by long-range PCR in the patient and mother, who carried the same mutation by segregation. We identified six intronic variants that were shared by the two genomes and not reported in the dbSNP(132) database. Among these, c.1236-405C>T located in IVS11 was predicted to be pathogenic because it affected splicing. This mutation creates a cryptic novel donor (5') splice site (score 1.00) 405 bp upstream of the exon 12 acceptor (3') splice site. cDNA analysis showed the inclusion of a 212-bp non-coding 'pseudoexon' with a premature stop codon. We validated the functional effect of the splicing mutation using a minigene assay. Using antisense morpholino oligonucleotides, designed to mask the cryptic donor splice-site created by the c.1236-405C>T mutation, we abrogated the aberrant splicing product to a wild-type ATM transcript, and in vitro reverted the functional ATM kinase impairment of the patients' lymphoblasts. Resequencing is an effective strategy for identifying rare splicing mutations in patients for whom other mutation analyses have failed (DHPLC, MLPA, or cDNA sequencing). This is especially important because many of these patients will carry rare splicing variants that are amenable to antisense-based correction.
Nouri N, Nouri N, Aryani O, et al. A novel mutation in the aprataxin (APTX) gene in an Iranian individual suffering early-onset ataxia with oculomotor apraxia type 1(AOA1) disease. Iran Biomed J. 2012; 16(4):223-5 [PubMed] Free Access to Full ArticleRelated Publications
BACKGROUND: Ataxia with oculomotor apraxia type 1 (AOA1) shows early onset with autosomal recessive inheritance and is caused by a mutation in the aprataxin (APTX) gene encoding for the APTX protein. METHODS: In this study, a 7-year-old girl born of a first-cousin consanguineous marriage was described with early-onset progressive ataxia and AOA, with increased cholesterol concentration and decreased albumin concentration in serum. PCR and direct DNA sequencing was performed after DNA extraction. RESULTS: Sequencing analysis revealed a novel homozygous deletion in c.643 and A>T single nucleotide polymorphism in c.641 in exon 6 of the APTX gene [ENST00000379825]. CONCLUSION: It seems that this region of exon 6 is probably a hot spot; however, no deletions have been reported in exon 6 yet.
Worth PF, Srinivasan V, Smith A, et al. Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia. Mov Disord. 2013; 28(4):524-8 [PubMed] Related Publications
BACKGROUND: The major clinical feature of ataxia telangiectasia (A-T) is severe progressive neurodegeneration with onset in infancy. This classical A-T phenotype is caused by biallelic null mutations in the ATM gene, leading to the absence of ATM protein and increased cellular radiosensitivity. We report an unusual case of A-T in a 41-year-old mother, A-T210, who had very mild neurological symptoms despite complete loss of ATM protein. METHODS: A neurological examination was performed, cellular radiosensitivity was assessed, and the ATM gene was sequenced. Skin fibroblasts and a lymphoblastoid cell line (LCL) were assayed for ATM protein expression and kinase activity. RESULTS: Patient A-T210 showed mild chorea, dystonia, and gait ataxia, walked independently, and drove a car. LCL and skin fibroblasts were radiosensitive and did not express ATM protein. Two ATM-null mutations were identified. CONCLUSIONS: The severe neurodegeneration resulting from loss of ATM can be mitigated in some circumstances.
The Mre11 complex (Mre11-Rad50-Nbs1 or MRN) binds double-strand breaks where it interacts with CtIP/Ctp1/Sae2 and ATM/Tel1 to preserve genome stability through its functions in homology-directed repair, checkpoint signaling and telomere maintenance. Here, we combine biochemical, structural and in vivo functional studies to uncover key properties of Mre11-W243R, a mutation identified in two pediatric cancer patients with enhanced ataxia telangiectasia-like disorder. Purified human Mre11-W243R retains nuclease and DNA binding activities in vitro. X-ray crystallography of Pyrococcus furiosus Mre11 indicates that an analogous mutation leaves the overall Mre11 three-dimensional structure and nuclease sites intact but disorders surface loops expected to regulate DNA and Rad50 interactions. The equivalent W248R allele in fission yeast allows Mre11 to form an MRN complex that efficiently binds double-strand breaks, activates Tel1/ATM and maintains telomeres; yet, it causes hypersensitivity to ionizing radiation and collapsed replication forks, increased Rad52 foci, defective Chk1 signaling and meiotic failure. W248R differs from other ataxia telangiectasia-like disorder analog alleles by the reduced stability of its interaction with Rad50 in cell lysates. Collective results suggest a separation-of-function mutation that disturbs interactions amongst the MRN subunits and Ctp1 required for DNA end processing in vivo but maintains interactions sufficient for Tel1/ATM checkpoint and telomere maintenance functions.
Piaceri I, Bagnoli S, Tedde A, et al. Ataxia-telangiectasia mutated (ATM) genetic variant in Italian centenarians. Neurol Sci. 2013; 34(4):573-5 [PubMed] Related Publications
Lifespan is attributable to genetic factors and some studies have attempted to identify putative genes implicated in human longevity. Several genetic loci have been associated with longevity, but some of these are not replicable, probably due to the vast differences among ethnicities. We analyzed in 128 Italian long-lived individuals and 150 unrelated healthy subjects, the recently reported association between rs189037 in the ataxia-telangiectasia mutated gene promoter and longevity in Chinese nonagenarians/centenarians. Our study confirms the association between the rs189037 C/T genotype and longevity in Italian centenarians, with an odds ratio of 1.85 (95 % CI 0.99-3.45). To understand the genetic basis for longevity is an extraordinarily difficult task, and therefore it is important to replicate any positive findings, especially if detected in other ethnic groups, in order to reach reliable conclusions on the real effect that candidate genes have on longevity.
The fourteenth international Ataxia-Telangiectasia Workshop 2012 (ATW2012) (www.atw2012.com) on ataxia-telangiectasia (AT) and the role of the ataxia telangiectasia mutated (ATM) gene in DNA repair, neurological disease, cancer and related topics was held from February 07 to 11, 2012 in Delhi, India. The international ATW2012 meeting reported the latest advances in ATM research as well as potential therapeutic treatments for A-T. The meeting was attended by a productive mix of scientists, ranging from those prominent in the initial characterization of the underlying genetic defect to young scientists just entering the field. In broad terms, three main themes were discussed at the meeting: first, a wealth of new details emerged on DNA damage signaling/repair mechanisms for which ATM is a critical element; secondly, important functions for ATM in previously unrelated cellular pathways were identified; and thirdly, new physiological effects and potential therapeutic treatments related to A-T were presented. This report summarizes below a sampling of the many interesting results from the meeting.