Journal Article

Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings

Enßen, Julia, Pietrucha, Barbara, Bogdanova, Natalia Valerijevna, Geffers, Robert, Wieland, Britta, Dörk, Thilo, Heropolitańska-Pliszka, Edyta

2017

Overview

Germline mutations in the RING finger protein gene have been identified in a combined immunodeficiency disorder called RIDDLE syndrome. Since only two patients have been described with somewhat different phenotypes, there is need to identify further patients. Here, we report on two Polish siblings with RNF168 deficiency due to homozygosity for a novel frameshift mutation, c.295delG, that was identified through exome sequencing. Both patients presented with immunoglobulin deficiency, telangiectasia, cellular radiosensitivity, and increased alpha-fetoprotein (AFP) levels. The younger sibling had a more pronounced neurological and morphological phenotype, and she also carried an gene mutation in the heterozygous state. Immunoblot analyses showed absence of RNF168 protein, whereas ATM levels and function were proficient in lymphoblastoid cells from both patients. Consistent with the absence of RNF168 protein, 53BP1 recruitment to DNA double-strand breaks (DSBs) after irradiation was undetectable in lymphoblasts or primary fibroblasts from either of the two patients. γH2AX foci accumulated normally but they disappeared with significant delay, indicating a severe defect in DSB repair. A comparison with the two previously identified patients indicates immunoglobulin deficiency, cellular radiosensitivity, and increased AFP levels as hallmarks of RNF168 deficiency. The variability in its clinical expression despite similar cellular phenotypes suggests that some manifestations of RNF168 deficiency may be modified by additional genetic or epidemiological factors.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Age / Ataxia / Ataxia telangiectasia mutated protein / Biopsy / Bronchitis / Case reports / Cell culture / chromosome instability / DNA damage / DNA repair / double-strand break repair / Epidemiology / Fibroblasts / Frameshift mutation / Gait / Genetic testing / Hospitalization / Immune system / Immunodeficiency / immunodeficiency syndrome / Immunology / Infections / Lesions / Lymphoblasts / Mutation / Patients / Phenotypes / Point mutation / Radiosensitivity / RING finger proteins / Siblings / Sinusitis / Skin / Whole genome sequencing / α-Fetoprotein