title: Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder.
abstract: 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).
authors.affiliation: Clinics of Obstetrics and Gynaecology, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Waltes
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kalb
authors.forename: Magtouf
authors.initials: M
authors.lastname: Gatei
authors.forename: Amanda W
authors.initials: AW
authors.lastname: Kijas
authors.forename: Markus
authors.initials: M
authors.lastname: Stumm
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sobeck
authors.forename: Britta
authors.initials: B
authors.lastname: Wieland
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Lerenthal
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
mesh_terms: D017766:Acid Anhydride Hydrolases; D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D043171:Chromosomal Instability; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D049932:Nijmegen Breakage Syndrome / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes