CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome
Abstract The CCC complex, composed of CCDC22, CCDC93, and ten proteins of the COMMD family, coordinates several critical steps required to recycle internalized plasma membrane proteins from endosomes to the cell surface. CCC interacts with Retriever, a trimeric cargo recognition complex comprising V...
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BMC
2025-05-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-025-02168-7 |
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| author | Amika Singla Carolyn Rogers Mary-Joe Touma Yassin El-Najjar Alison Colley Daniel J. Boesch Daniel D. Billadeau Jozef Gecz Baoyu Chen Ezra Burstein |
| author_facet | Amika Singla Carolyn Rogers Mary-Joe Touma Yassin El-Najjar Alison Colley Daniel J. Boesch Daniel D. Billadeau Jozef Gecz Baoyu Chen Ezra Burstein |
| author_sort | Amika Singla |
| collection | DOAJ |
| description | Abstract The CCC complex, composed of CCDC22, CCDC93, and ten proteins of the COMMD family, coordinates several critical steps required to recycle internalized plasma membrane proteins from endosomes to the cell surface. CCC interacts with Retriever, a trimeric cargo recognition complex comprising VPS35L, VPS26C, and VPS29, and works closely with the WASH complex, a crucial regulator of branched actin polymerization at endosomal membranes. Mutations in genes encoding subunits of these three complexes, CCDC22, VPS35L, and WASHC5, have been linked with a developmental syndrome known as 3 C (cranio-cerebello-cardiac) or Ritscher-Schinzel syndrome. Here, we report a new CCDC22 missense mutation, p.E208K, that results in attenuated 3 C syndrome, without cardiac or neuroanatomical abnormalities. We show that this mutation impairs CCC complex assembly by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding. We also review previously described cases and identify that CCDC22 p.P172R has a similar attenuated phenotype and impairs complex assembly in a similar fashion as p.E208K. The characterization of these mutations adds to our understanding of the clinical and molecular spectrum of these disorders. |
| format | Article |
| id | doaj-art-78d871e4d3cd472ea438e9098122c087 |
| institution | OA Journals |
| issn | 1755-8794 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | BMC Medical Genomics |
| spelling | doaj-art-78d871e4d3cd472ea438e9098122c0872025-08-20T02:38:31ZengBMCBMC Medical Genomics1755-87942025-05-0118111110.1186/s12920-025-02168-7CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndromeAmika Singla0Carolyn Rogers1Mary-Joe Touma2Yassin El-Najjar3Alison Colley4Daniel J. Boesch5Daniel D. Billadeau6Jozef Gecz7Baoyu Chen8Ezra Burstein9Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical CenterGenetics of Learning Disability Service, Hunter GeneticsDepartment of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical CenterDepartment of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical CenterGenetics of Learning Disability Service, Hunter GeneticsRoy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State UniversityDivision of Oncology Research, Mayo Clinic College of MedicineNeurogenetics Research Program, School of Pediatrics and Reproductive Health, University of AdelaideRoy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State UniversityDepartment of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical CenterAbstract The CCC complex, composed of CCDC22, CCDC93, and ten proteins of the COMMD family, coordinates several critical steps required to recycle internalized plasma membrane proteins from endosomes to the cell surface. CCC interacts with Retriever, a trimeric cargo recognition complex comprising VPS35L, VPS26C, and VPS29, and works closely with the WASH complex, a crucial regulator of branched actin polymerization at endosomal membranes. Mutations in genes encoding subunits of these three complexes, CCDC22, VPS35L, and WASHC5, have been linked with a developmental syndrome known as 3 C (cranio-cerebello-cardiac) or Ritscher-Schinzel syndrome. Here, we report a new CCDC22 missense mutation, p.E208K, that results in attenuated 3 C syndrome, without cardiac or neuroanatomical abnormalities. We show that this mutation impairs CCC complex assembly by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding. We also review previously described cases and identify that CCDC22 p.P172R has a similar attenuated phenotype and impairs complex assembly in a similar fashion as p.E208K. The characterization of these mutations adds to our understanding of the clinical and molecular spectrum of these disorders.https://doi.org/10.1186/s12920-025-02168-73 C syndromeCCDC22COMMD proteinRetrieverRitscher-Schinzel syndrome |
| spellingShingle | Amika Singla Carolyn Rogers Mary-Joe Touma Yassin El-Najjar Alison Colley Daniel J. Boesch Daniel D. Billadeau Jozef Gecz Baoyu Chen Ezra Burstein CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome BMC Medical Genomics 3 C syndrome CCDC22 COMMD protein Retriever Ritscher-Schinzel syndrome |
| title | CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome |
| title_full | CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome |
| title_fullStr | CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome |
| title_full_unstemmed | CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome |
| title_short | CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome |
| title_sort | ccdc22 mutations that impair commd binding cause attenuated 3c ritscher schinzel syndrome |
| topic | 3 C syndrome CCDC22 COMMD protein Retriever Ritscher-Schinzel syndrome |
| url | https://doi.org/10.1186/s12920-025-02168-7 |
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