Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the <i>CCDC88C</i> Gene
Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the <i>CCDC88C</i> gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| author | Fanni Annamária Boros László Szpisjak Renáta Bozó Evelyn Kelemen Dénes Zádori András Salamon Judit Danis Tibor Kalmár Zoltán Maróti Mária Judit Molnár Péter Klivényi Márta Széll Éva Ádám |
| author_facet | Fanni Annamária Boros László Szpisjak Renáta Bozó Evelyn Kelemen Dénes Zádori András Salamon Judit Danis Tibor Kalmár Zoltán Maróti Mária Judit Molnár Péter Klivényi Márta Széll Éva Ádám |
| author_sort | Fanni Annamária Boros |
| collection | DOAJ |
| description | Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the <i>CCDC88C</i> gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is a report of a patient with early-onset spastic paraparesis as well. Here, we describe a novel missense <i>CCDC88C</i> mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the <i>CCDC88C</i> gene that was identified in a female patient who developed late-onset ataxia, dysmetria and intention tremor. To explore the molecular consequences of the newly identified and previously described <i>CCDC88C</i> mutations, we carried out in vitro functional tests. The <i>CCDC88C</i> alleles were expressed in HEK293 cells, and the impact of the mutant DAPLE protein variants on JNK pathway activation and apoptosis was assessed. Our results revealed only a small-scale activation of the JNK pathway by mutant DAPLE proteins; however, increased JNK1 phosphorylation could not be detected. Additionally, none of the examined mutations triggered proapoptotic effect. In conclusion, we identified a novel mutation of the <i>CCDC88C</i> gene from a patient with spinocerebellar ataxia. Our results are not in accord with previous observations and do not support the primary role of the <i>CCDC88C</i> mutations in induction of JNK pathway activation in ataxia. Therefore, we propose that <i>CCDC88C</i> mutations may exert their effects through different and possibly in much broader, yet unexplored, biological processes. |
| first_indexed | 2024-03-11T09:41:23Z |
| format | Article |
| id | doaj.art-ecbd44b5778e4e0581cb4815948338e9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:41:23Z |
| publishDate | 2023-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ecbd44b5778e4e0581cb4815948338e92023-11-16T16:59:51ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243261710.3390/ijms24032617Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the <i>CCDC88C</i> GeneFanni Annamária Boros0László Szpisjak1Renáta Bozó2Evelyn Kelemen3Dénes Zádori4András Salamon5Judit Danis6Tibor Kalmár7Zoltán Maróti8Mária Judit Molnár9Péter Klivényi10Márta Széll11Éva Ádám12Department of Neurology, University of Szeged, 6720 Szeged, HungaryDepartment of Neurology, University of Szeged, 6720 Szeged, HungaryDepartment of Dermatology and Allergology, University of Szeged, 6720 Szeged, HungaryDepartment of Dermatology and Allergology, University of Szeged, 6720 Szeged, HungaryDepartment of Neurology, University of Szeged, 6720 Szeged, HungaryDepartment of Neurology, University of Szeged, 6720 Szeged, HungaryELKH-SZTE Dermatological Research Group, Eötvös Loránd Research Network, 6720 Szeged, HungaryGenetic Diagnostic Laboratory, Department of Pediatrics and Pediatric Healthy Care Center, University of Szeged, 6720 Szeged, HungaryGenetic Diagnostic Laboratory, Department of Pediatrics and Pediatric Healthy Care Center, University of Szeged, 6720 Szeged, HungaryInstitute of Genomic Medicine and Rare Disorders, Semmelweis University, 1082 Budapest, HungaryDepartment of Neurology, University of Szeged, 6720 Szeged, HungaryDepartment of Medical Genetics, University of Szeged, 6720 Szeged, HungaryDepartment of Medical Genetics, University of Szeged, 6720 Szeged, HungarySpinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the <i>CCDC88C</i> gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is a report of a patient with early-onset spastic paraparesis as well. Here, we describe a novel missense <i>CCDC88C</i> mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the <i>CCDC88C</i> gene that was identified in a female patient who developed late-onset ataxia, dysmetria and intention tremor. To explore the molecular consequences of the newly identified and previously described <i>CCDC88C</i> mutations, we carried out in vitro functional tests. The <i>CCDC88C</i> alleles were expressed in HEK293 cells, and the impact of the mutant DAPLE protein variants on JNK pathway activation and apoptosis was assessed. Our results revealed only a small-scale activation of the JNK pathway by mutant DAPLE proteins; however, increased JNK1 phosphorylation could not be detected. Additionally, none of the examined mutations triggered proapoptotic effect. In conclusion, we identified a novel mutation of the <i>CCDC88C</i> gene from a patient with spinocerebellar ataxia. Our results are not in accord with previous observations and do not support the primary role of the <i>CCDC88C</i> mutations in induction of JNK pathway activation in ataxia. Therefore, we propose that <i>CCDC88C</i> mutations may exert their effects through different and possibly in much broader, yet unexplored, biological processes.https://www.mdpi.com/1422-0067/24/3/2617SCA40CCDC88C mutationJNK pathwayapoptosisataxia |
| spellingShingle | Fanni Annamária Boros László Szpisjak Renáta Bozó Evelyn Kelemen Dénes Zádori András Salamon Judit Danis Tibor Kalmár Zoltán Maróti Mária Judit Molnár Péter Klivényi Márta Széll Éva Ádám Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the <i>CCDC88C</i> Gene International Journal of Molecular Sciences SCA40 CCDC88C mutation JNK pathway apoptosis ataxia |
| title | Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the <i>CCDC88C</i> Gene |
| title_full | Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the <i>CCDC88C</i> Gene |
| title_fullStr | Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the <i>CCDC88C</i> Gene |
| title_full_unstemmed | Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the <i>CCDC88C</i> Gene |
| title_short | Spinocerebellar Ataxia in a Hungarian Female Patient with a Novel Variant of Unknown Significance in the <i>CCDC88C</i> Gene |
| title_sort | spinocerebellar ataxia in a hungarian female patient with a novel variant of unknown significance in the i ccdc88c i gene |
| topic | SCA40 CCDC88C mutation JNK pathway apoptosis ataxia |
| url | https://www.mdpi.com/1422-0067/24/3/2617 |
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