Human RAD50 Deficiency in a Nijmegen Breakage Syndrome-like Disorder
| Autor: | Magtouf Gatei, Raymonda Varon, Britta Wieland, Reinhard Kalb, Detlev Schindler, Thilo Dörk, Markus Stumm, Martin F. Lavin, Yaniv Lerenthal, Regina Waltes, Alexandra Sobeck, Amanda W. Kijas |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Adult
Microcephaly Heterozygote DNA repair Cell Survival Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Biology Protein Serine-Threonine Kinases Compound heterozygosity Short stature Radiation Tolerance Article Chromosome instability Chromosomal Instability medicine Genetics Humans Genetics(clinical) Genetic Predisposition to Disease Nijmegen Breakage Syndrome Genetics (clinical) Cells Cultured Germ-Line Mutation Tumor Suppressor Proteins Genetic disorder medicine.disease Acid Anhydride Hydrolases DNA-Binding Proteins enzymes and coenzymes (carbohydrates) DNA Repair Enzymes Rad50 Cancer research Female medicine.symptom biological phenomena cell phenomena and immunity Nijmegen breakage syndrome DNA Damage Signal Transduction |
| Popis: | The MRE11/RAD50/NBN (MRN) complex plays a key role in recognizing and signaling DNA double-strand breaks (DSBs). Hypomorphic mutations in NBN (previously known as NBS1) and MRE11A give rise to the autosomal-recessive diseases Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD), respectively. To date, no disease due to RAD50 deficiency has been described. Here, we report on a patient previously diagnosed as probably having NBS, with microcephaly, mental retardation, ‘bird-like’ face, and short stature. At variance with this diagnosis, she never had severe infections, had normal immunoglobulin levels, and did not develop lymphoid malignancy up to age 23 years. We found that she is compound heterozygous for mutations in the RAD50 gene that give rise to low levels of unstable RAD50 protein. Cells from the patient were characterized by chromosomal instability; radiosensitivity; failure to form DNA damage-induced MRN foci; and impaired radiation-induced activation of and downstream signaling through the ATM protein, which is defective in the human genetic disorder ataxia-telangiectasia. These cells were also impaired in G1/S cell-cycle-checkpoint activation and displayed radioresistant DNA synthesis and G2-phase accumulation. The defective cellular phenotype was rescued by wild-type RAD50. In conclusion, we have identified and characterized a patient with a RAD50 deficiency that results in a clinical phenotype that can be classified as an NBS-like disorder (NBSLD). |
| Databáze: | OpenAIRE |
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