RRC ID 77523
Author Takagi M, Hoshino A, Bousset K, Röddecke J, Martin HL, Folcut I, Tomomasa D, Yang X, Kobayashi J, Sakata N, Yoshida K, Miyano S, Ogawa S, Kojima S, Morio T, Dörk T, Kanegane H.
Title Bone Marrow Failure and Immunodeficiency Associated with Human RAD50 Variants.
Journal J Clin Immunol
Abstract PURPOSE:The MRE11-RAD50-NBN (MRN) complex plays a key role in recognizing and signaling DNA double-strand breaks. Pathogenic variants in NBN and MRE11 give rise to the autosomal-recessive diseases, Nijmegen breakage syndrome (NBS) and ataxia telangiectasia-like disorder, respectively. The clinical consequences of pathogenic variants in RAD50 are incompletely understood. We aimed to characterize a newly identified RAD50 deficiency/NBS-like disorder (NBSLD) patient with bone marrow failure and immunodeficiency.
METHODS:We report on a girl with microcephaly, mental retardation, bird-like face, short stature, bone marrow failure and B-cell immunodeficiency. We searched for candidate gene by whole-exome sequencing and analyzed the cellular phenotype of patient-derived fibroblasts using immunoblotting, radiation sensitivity assays and lentiviral complementation experiments.
RESULTS:Compound heterozygosity for two variants in the RAD50 gene (p.Arg83His and p.Glu485Ter) was identified in this patient. The expression of RAD50 protein and MRN complex formation was maintained in the cells derived from this patient. DNA damage-induced activation of the ATM kinase was markedly decreased, which was restored by the expression of wild-type (WT) RAD50. Radiosensitivity appeared inconspicuous in the patient-derived cell line as assessed by colony formation assay. The RAD50R83H missense substitution did not rescue the mitotic defect in complementation experiments using RAD50-deficient fibroblasts, whereas RAD50WT did. The RAD50E485X nonsense variant was associated with in-frame skipping of exon 10 (p.Glu485_545del).
CONCLUSION:These findings indicate important roles of RAD50 in human bone marrow and immune cells. RAD50 deficiency/NBSLD can manifest as a distinct inborn error of immunity characterized by bone marrow failure and B-cell immunodeficiency.
Volume 43(8)
Pages 2136-2145
Published 2023-11-1
DOI 10.1007/s10875-023-01591-8
PII 10.1007/s10875-023-01591-8
PMID 37794136
MeSH Ataxia Telangiectasia Mutated Proteins / genetics Bone Marrow Failure Disorders Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Female Humans Immunologic Deficiency Syndromes* / diagnosis Immunologic Deficiency Syndromes* / genetics MRE11 Homologue Protein / genetics MRE11 Homologue Protein / metabolism Nijmegen Breakage Syndrome* / genetics Protein Serine-Threonine Kinases / genetics Tumor Suppressor Proteins / genetics
DNA material CSII-CMV-MCS-IRES2-Bsd (RDB04385)