Human RAD50 deficiency: Confirmation of a distinctive phenotype

Aviël Ragamin, Gökhan Yigit, Kristine Bousset, Filippo Beleggia, Frans W. Verheijen, Marie Claire Y. de Wit, Tim M. Strom, Thilo Dörk, Bernd Wollnik, Grazia M.S. Mancini*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Scopus)


DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)-like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS-like disorder. Here, we report a long-term follow-up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient-derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the patient-derived fibroblasts and provided evidence for a markedly reduced radiation-induced AT-mutated signaling. Comparison with the previously reported case and with patients presenting with NBS confirms that RAD50 mutations lead to a similar, but distinctive phenotype.

Original languageEnglish
Pages (from-to)1378-1386
Number of pages9
JournalAmerican Journal of Medical Genetics, Part A
Issue number6
Publication statusPublished - 1 Jun 2020

Bibliographical note

Funding Information:
The authors thank our proband and her family for their collaboration in this study. The authors thank Marianne Doornbos for patient care and Detlev Schindler for his seminal contribution of fibroblast cell lines. G. M. S. M. is supported by the ZonMW Top grant # 91217045.

Publisher Copyright:
© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.

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