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Ataxia-telangiectasia
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Ataxia-telangiectasia (A-T)
Background
"Localization of an ataxia-telangiectasia gene to chromosome 11q22–23"(1)
Background
- Ataxia–telangiectasia (A–T) or Louis–Bar syndrome is an inherited neurodegenerative disease.(2)
- Ataxia = poor coordination , telangiectasia = small dilated blood vessels.(2)
- It’s caused by mutations in the ATM gene which encodes an ATM protein.(2)
- The gene is located on chromosome 11 (11q22.3).(1)
Symptoms and Treatments
Symptoms and treatments
Digestion (2,3)
Immunity (2,3)
Neurological impairments (2,3)
Vision (2,3)
Orthopaedics (2,3)
Diagnosis
Clinical symptoms (4)
Molecular testing (4)
Gene identification
"A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase"(5)
Gene Identification
- Gern JE.
- Published on the 23d of June 1995, Pediatrics Journal.
- This study was conducted to identify the gene causing A-T (ATM) by positional cloning on chromosome 11 q22-2.
Positional Cloning
Positional cloning
Figure 1. Positional cloning of the AT candidate gene.(5)
Gene expression
Gene expression
Figure 2. Expression of the ATM gene. A 5-kb 12- probe spanning the ORF of the 7-9 cDNA was hybridized to RNA.(5)
Figure 3. Amino acid sequence (50) of the deduced translation product encoded by the ORF in cDNA clone 7-9, beginning with the first available methionine residue.(5)
Identfied mutations
Table 1. Mutations identified in the ATM gene in AT patients.(5)
Identfied mutations
Representative P1-3 kinases
Figure 4. Schematic diagram of representative Pl-3 kinases.(5)
Gene deletion
Figure 5. A deletion in the gene corresponding to the 7-9 transcript in family ISAT 9.(5)
Mechanism of the mutation
"Comprehensive scanning of the ATM gene with DOVAM-S"(6)
Mechanism of the mutation
- Buzin CH, Gatti RA, Nguyen VQ, Wen CY, Mitui M, Sanal O, et al.
- Published on the 9th of August 2003, Human Mutation Journal.
- This study was conducted to scan the entire coding region of ATM and the adjacent intronic regions by using Detection Of Virtually All Mutations-SSCP (DOVAM-S) for the detection of A-T causing mutations.
ATM sequences scanned
ATM sequences scanned
Table 2. ATM Sequence Scanned.(6)
Mutations detected
Table 3. Mutations Detected in A-T Patients and Obligate Carriers.(6)
Mutations detected
Mutant alleles detected
Table 4. ATM Mutant Alleles in A-T Patients and Carriers.(6)
Mutant alleles detected
Polymorphisms detected
Table 5. ATM Polymorphisms Detected.(6)
Polymorphisms detected
Cellular pathway (cell cycle regulation)
Cellular Pathways
Figure 6. Overview of ATM and ATR dependent DNA damage induced cell cycle checkpoint signalling.(7)
Transmission and Epidemiology
Transmission and Population Frequency
Founders effect (2)
Autosomal Recessive (2)
Incidence ranges from 1:40,000 to 1:100,000 (2)
Gene Therapy
"Reconstitution of the Ataxia-Telangiectasia Cellular Phenotype With Lentiviral Vectors"(8)
Gene Therapy
- Carranza D, Torres-Rusillo S, Ceballos-Pérez G, Blanco-Jimenez E, Muñoz-López M, García-Pérez JL, et al.
- Published on the 20th of August 2018, Fronteirs in Immunology Journal.
- The study was conducted to rescue the intrinsic cellular defects caused by ATM mutations (in A-T human mutant fibroblasts) for the production of functional ATM proteins.
Expressing functional protein
Expressing functional protein
Figure 7. Construction and expression of a lentiviral vector containing a normal ATM cDNA.(8)
Figure 8. Accumulation of p-ATM foci in A-T HIFs transduced with the lentiviral vector ThATM.(8)
Repairing irradiation-induced DSBs
Repairing irradiation-induced DSBs
Figure 9. Foci formation of p-p53 in WT and A-T HIFs transduced with the ThATM lentiviral vector.(8)
Research Directions
"Ataxia-Telangiectasia Mutated Is Involved in Autolysosome Formation"(9)
Research Directions
- Hwang M, Jun DW, Song BR, Shim H, Lee C-H, Kim S.
- Published on the 7th of January 2023, Biomolecules & Therapeutics Journal.
- HeLa cells were transfected with siRNA targeting ATM.
- ATM inhibition blocked autolysosome formation.
- Accumulation of autophagosomes caused by ATM inhibition induced cell death.
- These results could expand the use of ATM inhibitors as potential combinational cancer drugs.
References
References
1. Gatti RA, Bick M, Tam CF, Medici MA, Oxelius V-A, Holland M, et al. Ataxia-telangiectasia: A multiparameter analysis of eight families. Clinical Immunology and Immunopathology. 1982 Dec 29;23(2):501–16. doi:10.1016/0090-1229(82)90134-9
2. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: A Review. Orphanet Journal of Rare Diseases. 2016 Nov 25;11(1). doi:10.1186/s13023-016-0543-7
3. BioRENDER. Scientific Image and Illustration Software [Internet]. 2023 [cited 2023 Oct 12]. Available from: https://www.biorender.com/
4. Gatti RA. Ataxia-telangiectasia. Dermatologic Clinics. 1995 Mar 23;13(1):1–6. doi:10.1016/s0733-8635(18)30100-1
5. Gern JE. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Pediatrics. 1996 Apr 1;98(2):350–350. doi:10.1542/peds.98.2.350a
6. Buzin CH, Gatti RA, Nguyen VQ, Wen CY, Mitui M, Sanal O, et al. Comprehensive scanning of theatm gene with Dovam-S. Human Mutation. 2003 Aug 9;21(2):123–31. doi:10.1002/humu.10158
7. Weber AM, Ryan AJ. ATM and ATR as therapeutic targets in cancer. Pharmacology & Therapeutics. 2015 Dec 1;149:124–38. doi:10.1016/j.pharmthera.2014.12.001
8. Carranza D, Torres-Rusillo S, Ceballos-Pérez G, Blanco-Jimenez E, Muñoz-López M, García-Pérez JL, et al. Reconstitution of the ataxia-telangiectasia cellular phenotype with lentiviral vectors. Frontiers in Immunology. 2018 Aug 20;9. doi:10.3389/fimmu.2018.02703
9. Hwang M, Jun DW, Song BR, Shim H, Lee C-H, Kim S. Ataxia-telangiectasia mutated is involved in Autolysosome Formation. Biomolecules & Therapeutics. 2023 Mar 21;31(5):559–65. doi:10.4062/biomolther.2023.003