Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome
Microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a neurodevelopmental disorder caused by the deficiency of the X-chromosomal gene CASK. However, the molecular mechanisms by which CASK deficiency causes cerebellar hypoplasia in this syndrome remain elusive. In this study, we u...
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MDPI AG
2023-04-01
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| author | Qi Guo Emi Kouyama-Suzuki Yoshinori Shirai Xueshan Cao Toru Yanagawa Takuma Mori Katsuhiko Tabuchi |
| author_facet | Qi Guo Emi Kouyama-Suzuki Yoshinori Shirai Xueshan Cao Toru Yanagawa Takuma Mori Katsuhiko Tabuchi |
| author_sort | Qi Guo |
| collection | DOAJ |
| description | Microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a neurodevelopmental disorder caused by the deficiency of the X-chromosomal gene CASK. However, the molecular mechanisms by which CASK deficiency causes cerebellar hypoplasia in this syndrome remain elusive. In this study, we used CASK knockout (KO) mice as models for MICPCH syndrome and investigated the effect of CASK mutants. Female CASK heterozygote KO mice replicate the progressive cerebellar hypoplasia observed in MICPCH syndrome. CASK KO cultured cerebellar granule (CG) cells show progressive cell death that can be rescued by co-infection with lentivirus expressing wild-type CASK. Rescue experiments with CASK deletion mutants identify that the CaMK, PDZ, and SH3, but not L27 and guanylate kinase domains of CASK are required for the survival of CG cells. We identify missense mutations in the CaMK domain of CASK derived from human patients that fail to rescue the cell death of cultured CASK KO CG cells. Machine learning-based structural analysis using AlphaFold 2.2 predicts that these mutations disrupt the structure of the binding interface with Liprin-α2. These results suggest that the interaction with Liprin-α2 via the CaMK domain of CASK may be involved in the pathophysiology of cerebellar hypoplasia in MICPCH syndrome. |
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| language | English |
| last_indexed | 2024-03-11T05:09:01Z |
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| spelling | doaj.art-65c5aa1e4d2b4023b26efdea77ba4b132023-11-17T18:43:35ZengMDPI AGCells2073-44092023-04-01128117710.3390/cells12081177Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH SyndromeQi Guo0Emi Kouyama-Suzuki1Yoshinori Shirai2Xueshan Cao3Toru Yanagawa4Takuma Mori5Katsuhiko Tabuchi6Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, JapanDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, JapanDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, JapanCollege of Life Science and Oceanography, Shenzhen University, Shenzhen 518071, ChinaDepartment of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, JapanDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, JapanDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, JapanMicrocephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a neurodevelopmental disorder caused by the deficiency of the X-chromosomal gene CASK. However, the molecular mechanisms by which CASK deficiency causes cerebellar hypoplasia in this syndrome remain elusive. In this study, we used CASK knockout (KO) mice as models for MICPCH syndrome and investigated the effect of CASK mutants. Female CASK heterozygote KO mice replicate the progressive cerebellar hypoplasia observed in MICPCH syndrome. CASK KO cultured cerebellar granule (CG) cells show progressive cell death that can be rescued by co-infection with lentivirus expressing wild-type CASK. Rescue experiments with CASK deletion mutants identify that the CaMK, PDZ, and SH3, but not L27 and guanylate kinase domains of CASK are required for the survival of CG cells. We identify missense mutations in the CaMK domain of CASK derived from human patients that fail to rescue the cell death of cultured CASK KO CG cells. Machine learning-based structural analysis using AlphaFold 2.2 predicts that these mutations disrupt the structure of the binding interface with Liprin-α2. These results suggest that the interaction with Liprin-α2 via the CaMK domain of CASK may be involved in the pathophysiology of cerebellar hypoplasia in MICPCH syndrome.https://www.mdpi.com/2073-4409/12/8/1177MICPCH syndromeCASKLiprin-α2cerebellar granule cellsCaMK domain |
| spellingShingle | Qi Guo Emi Kouyama-Suzuki Yoshinori Shirai Xueshan Cao Toru Yanagawa Takuma Mori Katsuhiko Tabuchi Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome Cells MICPCH syndrome CASK Liprin-α2 cerebellar granule cells CaMK domain |
| title | Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome |
| title_full | Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome |
| title_fullStr | Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome |
| title_full_unstemmed | Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome |
| title_short | Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome |
| title_sort | structural analysis implicates cask liprin α2 interaction in cerebellar granular cell death in micpch syndrome |
| topic | MICPCH syndrome CASK Liprin-α2 cerebellar granule cells CaMK domain |
| url | https://www.mdpi.com/2073-4409/12/8/1177 |
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