Bone Marrow Failure and Immunodeficiency Associated with Human RAD50 Variants.
Female
Humans
Cell Cycle Proteins
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Tumor Suppressor Proteins
/ genetics
Ataxia Telangiectasia Mutated Proteins
/ genetics
MRE11 Homologue Protein
/ genetics
Nijmegen Breakage Syndrome
/ genetics
Immunologic Deficiency Syndromes
/ diagnosis
Bone Marrow Failure Disorders
Bone marrow failure
DNA double-strand breaks
MRE11/RAD50/NBN complex
Nijmegen breakage syndrome
RAD50 deficiency
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
23
11
2022
accepted:
20
09
2023
medline:
27
11
2023
pubmed:
5
10
2023
entrez:
4
10
2023
Statut:
ppublish
Résumé
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. 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. 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 RAD50 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.
Identifiants
pubmed: 37794136
doi: 10.1007/s10875-023-01591-8
pii: 10.1007/s10875-023-01591-8
doi:
Substances chimiques
Cell Cycle Proteins
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
Tumor Suppressor Proteins
0
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
MRE11 Homologue Protein
EC 3.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2136-2145Subventions
Organisme : MEXT/JSPS KAKENHI
ID : 22K07887
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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