Universität zu Köln

Ragamin, Aviel, Yigit, Goekhan, Bousset, Kristine, Beleggia, Filippo, Verheijen, Frans W., de Wit, Marie-Claire Y., Strom, Tim M., Doerk, Thilo, Wollnik, Bernd and Mancini, Grazia M. S. (2020). Human RAD50 deficiency: Confirmation of a distinctive phenotype. Am. J. Med. Genet. A, 182 (6). S. 1378 - 1387. HOBOKEN: WILEY. ISSN 1552-4833

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ragamin, Aviel UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Bousset, Kristine UNSPECIFIED UNSPECIFIED UNSPECIFIED Beleggia, Filippo UNSPECIFIED UNSPECIFIED UNSPECIFIED Verheijen, Frans W. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Wit, Marie-Claire Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Strom, Tim M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Doerk, Thilo UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Mancini, Grazia M. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-340289
DOI:	10.1002/ajmg.a.61570
Journal or Publication Title:	Am. J. Med. Genet. A
Volume:	182
Number:	6
Page Range:	S. 1378 - 1387
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1552-4833
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE; REPAIR; GENE; NBS1; INSTABILITY; DISRUPTION; MECHANISMS; MUTATIONS; LETHALITY; RESPONSES Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34028