Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings
Germline mutations in the RING finger protein gene RNF168 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 sib...
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| Format: | Article |
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Frontiers Media S.A.
2017-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01683/full |
| _version_ | 1823956399828238336 |
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| author | Barbara Pietrucha Edyta Heropolitańska-Pliszka Robert Geffers Julia Enßen Britta Wieland Natalia Valerijevna Bogdanova Natalia Valerijevna Bogdanova Thilo Dörk |
| author_facet | Barbara Pietrucha Edyta Heropolitańska-Pliszka Robert Geffers Julia Enßen Britta Wieland Natalia Valerijevna Bogdanova Natalia Valerijevna Bogdanova Thilo Dörk |
| author_sort | Barbara Pietrucha |
| collection | DOAJ |
| description | Germline mutations in the RING finger protein gene RNF168 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 ATM 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. |
| first_indexed | 2024-12-17T15:44:54Z |
| format | Article |
| id | doaj.art-46da44d39ed2478495113d5eb9ee531a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T15:44:54Z |
| publishDate | 2017-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-46da44d39ed2478495113d5eb9ee531a2022-12-21T21:42:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-12-01810.3389/fimmu.2017.01683304910Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish SiblingsBarbara Pietrucha0Edyta Heropolitańska-Pliszka1Robert Geffers2Julia Enßen3Britta Wieland4Natalia Valerijevna Bogdanova5Natalia Valerijevna Bogdanova6Thilo Dörk7Department of Immunology, Children’s Memorial Health Institute, Warsaw, PolandDepartment of Immunology, Children’s Memorial Health Institute, Warsaw, PolandGenome Analytics Unit, Helmholtz Center for Infection Research, Braunschweig, GermanyGynaecology Research Unit, Hannover Medical School, Hannover, GermanyGynaecology Research Unit, Hannover Medical School, Hannover, GermanyGynaecology Research Unit, Hannover Medical School, Hannover, GermanyRadiation Oncology Research Unit, Hannover Medical School, Hannover, GermanyGynaecology Research Unit, Hannover Medical School, Hannover, GermanyGermline mutations in the RING finger protein gene RNF168 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 ATM 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.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01683/fullDNA repairchromosome instabilityradiosensitivityimmunodeficiency syndromedouble-strand break repair |
| spellingShingle | Barbara Pietrucha Edyta Heropolitańska-Pliszka Robert Geffers Julia Enßen Britta Wieland Natalia Valerijevna Bogdanova Natalia Valerijevna Bogdanova Thilo Dörk Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings Frontiers in Immunology DNA repair chromosome instability radiosensitivity immunodeficiency syndrome double-strand break repair |
| title | Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings |
| title_full | Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings |
| title_fullStr | Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings |
| title_full_unstemmed | Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings |
| title_short | Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings |
| title_sort | clinical and biological manifestation of rnf168 deficiency in two polish siblings |
| topic | DNA repair chromosome instability radiosensitivity immunodeficiency syndrome double-strand break repair |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01683/full |
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