scholarly journals Six Novel ATM Gene Variants in Sri Lankan Patients with Ataxia Telangiectasia

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
D. Hettiarachchi ◽  
Hetalkumar Panchal ◽  
B. A. P. S. Pathirana ◽  
P. D. Rathnayaka ◽  
A. Padeniya ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Protein Structures ◽  
Compound Heterozygous ◽  
Sri Lankan ◽  
Gene Variants ◽  
Counseling And Testing ◽  
Whole Exome ◽  
Progressive Ataxia ◽  
Atm Gene ◽  
Atm Protein

Introduction. Ataxia telangiectasia is a rare genetic condition with an estimated prevalence of 1 in 40,000–100,000 live births. This condition predominantly affects the nervous and immune systems. It is characterized by progressive ataxia beginning from early childhood. The neurological deficit associated with this condition affects one’s balance, coordination, walking, and speech and can be accompanied by chorea, myoclonus, and neuropathy. They may also have ocular telangiectasias and high levels of blood alpha-fetoprotein (AFP). The ataxia telangiectasia mutated gene (ATM) is associated with this condition and codes for the ATM protein which is a phosphatidylinositol 3-kinase. This gene occupies 150 kb on chromosome 11q22–23 and contains 66 exons encoding a 13 kb transcript. ATM is a relatively large protein with a molecular weight of 350 kDa and 3,056 amino acids. Methods. Four patients of Sri Lankan origin presenting with features suggestive of ataxia telangiectasia were referred to our genetics center for specialized genetic counseling and testing. Whole-exome sequencing followed by Sanger sequencing was used to confirm the candidate variants. Protein modeling and genotype to phenotype correlation was performed in the identified variants. Results. We observed 6 novel ATM gene variants in four patients with ataxia telangiectasia. The identified variants are as follows: homozygous c.7397C > A (p.Ala2466Glu) and c.510_511delGT (p.Tyr171fs) and compound heterozygous c.5347_5350delGAAA (p.Glu1783fs), c.8137A > T (p.Arg2713 ∗ ) and c.1163A > C (p.Lys388Thr), and c.5227A > C (p.Thr1743Pro). Variant analysis was followed by modeling of the native and altered protein structures. Conclusion. We report novel ATM gene variants that have implications on the molecular diagnosis of ataxia telangiectasia.

Correction of ATM mutations in iPS cells from two ataxia-telangiectasia patients restores DNA damage and oxidative stress responses

2020 ◽  
Vol 29 (6) ◽  
pp. 990-1001 ◽  
Author(s):  
Dmitry A Ovchinnikov ◽  
Sarah L Withey ◽  
Hannah C Leeson ◽  
U Wang Lei ◽  
Ashmitha Sundarrajan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Stress Responses ◽  
Ataxia Telangiectasia ◽  
Compound Heterozygous ◽  
Gene Correction ◽  
Atm Kinase ◽  
Atm Protein ◽  
Induced Apoptosis ◽  
And Oxidative Stress

Abstract Patients with ataxia-telangiectasia (A-T) lack a functional ATM kinase protein and exhibit defective repair of DNA double-stranded breaks and response to oxidative stress. We show that CRISPR/Cas9-assisted gene correction combined with piggyBac (PB) transposon-mediated excision of the selection cassette enables seamless restoration of functional ATM alleles in induced pluripotent stem cells from an A-T patient carrying compound heterozygous exonic missense/frameshift mutations, and from a patient with a homozygous splicing acceptor mutation of an internal coding exon. We show that the correction of one allele restores expression of ~ 50% of full-length ATM protein and ameliorates DNA damage-induced activation (auto-phosphorylation) of ATM and phosphorylation of its downstream targets, KAP-1 and H2AX. Restoration of ATM function also normalizes radiosensitivity, mitochondrial ROS production and oxidative-stress-induced apoptosis levels in A-T iPSC lines, demonstrating that restoration of a single ATM allele is sufficient to rescue key ATM functions. Our data further show that despite the absence of a functional ATM kinase, homology-directed repair and seamless correction of a pathogenic ATM mutation is possible. The isogenic pairs of A-T and gene-corrected iPSCs described here constitute valuable tools for elucidating the role of ATM in ageing and A-T pathogenesis.

scholarly journals Identification of Two Novel Mutations in the ATM Gene from Patients with Ataxia-Telangiectasia by Whole Exome Sequencing

2020 ◽  
Vol 20 (7) ◽  
pp. 531-534
Author(s):  
Masoud Heidari ◽  
Morteza Soleyman-Nejad ◽  
Mohammad H. Taskhiri ◽  
Javad Shahpouri ◽  
Alireza Isazadeh ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ataxia Telangiectasia ◽  
Direct Sequencing ◽  
Genetic Diagnosis ◽  
Cell Cycle Checkpoints ◽  
Causative Mutation ◽  
Novel Mutations ◽  
Whole Exome ◽  
Atm Gene

Background: Ataxia telangiectasia (AT) is one of the most common autosomal recessive hereditary ataxia presenting in childhood. The responsible gene for AT designated ATM (AT, mutated) encodes a protein which is involved in cell cycle checkpoints and other responses to genotoxicity. We describe two novel disease-causing mutations in two unrelated Iranian families with Ataxiatelangiectasia. Methods: The probands including a 6-year-old female and an 18-year-old boy were diagnosed with Ataxia-telangiectasia among two different Iranian families. In this study, Whole-Exome Sequencing (WES) was employed for the detection of genetic changes in probands. The analysis of the cosegregation of the variants with the disease in families was conducted using PCR direct sequencing. Results: Two novel frameshift mutations, (c.4236_4236del p. Pro1412fs) and (c.8907T>G p. Tyr2969Ter) in the ataxia telangiectasia mutated ATM gene were detected using Whole-Exome Sequencing (WES) in the probands. These mutations were observed in two separate A-T families. Conclusion: Next-generation sequencing successfully identified the causative mutation in families with ataxia-telangiectasia. These novel mutations in the ATM gene reported in the present study could assist genetic counseling, Preimplantation Genetic Diagnosis (PGD) and prenatal diagnosis (PND) of AT.

Ataxia Telangiectasia Mutated (ATM) Gene Variants in American Indians

2010 ◽  
Vol 78 (3) ◽  
pp. S90 ◽  
Author(s):  
D.G. Petereit ◽  
A. Moser ◽  
J. Hahn ◽  
A. Boylan ◽  
S. Kanekar ◽  
...  
Keyword(s):  
American Indians ◽  
Ataxia Telangiectasia ◽  
Gene Variants ◽  
Ataxia Telangiectasia Mutated ◽  
Atm Gene

THE KNOWN UK CASES OF ATAXIA TELANGIECTASIA-LIKE DISORDER (ATLD)

2015 ◽  
Vol 86 (11) ◽  
pp. e4.184-e4
Author(s):  
Katy Westwood ◽  
John Ealing ◽  
Malcolm Taylor ◽  
Paul Worth ◽  
Andrea Nemeth
Keyword(s):  
Ataxia Telangiectasia ◽  
Genome Stability ◽  
Autosomal Recessive ◽  
Atm Kinase ◽  
Clinical Presentations ◽  
Progressive Ataxia ◽  
Atm Gene ◽  
Spontaneous Chromosome ◽  
The Uk ◽  
Rare Autosomal Recessive Disease

Ataxia telangiectasia-like disorder (ATLD) is a very rare autosomal recessive disease with only 25 patients recognised worldwide. ATLD is likened to Ataxia telangiectasia (A-T) due to an overlap of clinical presentations and cellular characteristics. The clinical hallmark of A-T and ATLD is progressive young onset cerebellar ataxia. Variably present characteristics include dysarthria, oculomotor apraxia, ocular telangiectasia, immunodeficiency, spontaneous chromosome abnormalities and a predisposition to malignancy. In contrast to A-T, ocular telangiectasia is absent. Furthermore, ATLD patients tend to have a later onset and slower progression of neurological signs than A-T. The ATM gene, that has a key role in genome stability, is mutated in A-T resulting in an increase cancer predisposition. In ATLD, gene MRE11 is mutated leading to deficient activation of ATM. A functional consequence of the MRE11 mutation is raised chromosomal radiosensitivity because functional ATM kinase is required to rejoin chromosome breaks. This poster/presentation will describe the clinical features and genetic analysis of the ATLD cases with progressive ataxia known in the UK. Undergraduate Prize Winner 2015

scholarly journals Immunoassay to Measure Ataxia-Telangiectasia Mutated Protein in Cellular Lysates

2004 ◽  
Vol 50 (12) ◽  
pp. 2302-2308 ◽  
Author(s):  
Anthony W Butch ◽  
Helen H Chun ◽  
Shareef A Nahas ◽  
Richard A Gatti
Keyword(s):  
Ataxia Telangiectasia ◽  
Mononuclear Cells ◽  
Lymphoblastoid Cell Lines ◽  
Ataxia Telangiectasia Mutated ◽  
Peripheral Blood Mononuclear ◽  
Neurologic Disorder ◽  
Increased Risk ◽  
Atm Gene ◽  
Atm Protein ◽  
Ataxia Telangiectasia Mutated Protein

Abstract Background: Ataxia-telangiectasia (A-T) is a neurologic disorder caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. A clinical diagnosis of A-T is confirmed by radiosensitivity testing and immunoblotting for ATM protein. Because both of these tests have long turnaround times (≥3 months), we developed a rapid immunoassay to measure ATM protein and determined its sensitivity and specificity for diagnosing A-T. Methods: Recombinant ATM protein was used for standardization. Lysates of lymphoblastoid cell lines (LCLs) and peripheral blood mononuclear cells (PBMCs) from A-T patients, controls, and A-T heterozygotes were tested for ATM protein by immunoassay. Results: Between-run imprecision (CV) was ≤13%. Nuclear lysates from control LCLs and PBMCs had ATM protein concentrations of 49–610 μg/L and 48–943 μg/L, respectively. ATM protein was not detectable in LCL nuclear lysates from 18 of 21 A-T patients. The three remaining A-T patients had trace amounts of ATM protein, which was confirmed on immuoblots. ATM protein was also detectable in whole-cell lysates from 4 × 106 cells at concentrations of 64–463 μg/L and 42–444 μg/L for control LCLs and PBMCs, respectively. A-T heterozygotes had ATM protein concentrations of 52–98 μg/L. ATM protein was stable in PBMCs stored for 1 month at −70 °C, but rapidly decreased after 1 day in unprocessed blood. Conclusions: This ATM protein immunoassay can be used to confirm a diagnosis of A-T in 2 days on small numbers of PBMCs and can potentially identify A-T carriers and individuals at increased risk for cancer.

scholarly journals A novel variant in ATM gene causes ataxia telangiectasia revealed by whole-exome sequencing

Neurosciences ◽  
2018 ◽  
Vol 23 (2) ◽  
pp. 162-164 ◽  
Author(s):  
Noufa Alonazi ◽  
Khalid Hundallah ◽  
Amal Al Hashem ◽  
Sarar Mohamed
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ataxia Telangiectasia ◽  
Whole Exome ◽  
Novel Variant ◽  
Atm Gene

scholarly journals Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Jong Seop Kim ◽  
Hyoungseok Jeon ◽  
Hyeran Lee ◽  
Jung Min Ko ◽  
Yonghwan Kim ◽  
...  
Keyword(s):  
Hip Dysplasia ◽  
Large Deletion ◽  
Compound Heterozygous ◽  
Radial Head Dislocation ◽  
Sequencing Data ◽  
Novel Mutations ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Carpal Coalition

AbstractAn 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome. Scrutinizing the trio whole-exome sequencing data revealed novel compound heterozygous mutations of COL27A1 (c.[4229_4233dup]; [3718_5436del], p.[Gly1412Argfs*157];[Gly1240_Lys1812del]) in the proband, which were inherited from heterozygous parents. The maternal mutation was a large deletion encompassing exons 38–60, which was challenging to detect.

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