CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome

被引：0

作者：

Amika Singla ^{[1
]}

Carolyn Rogers ^{[2
]}

Mary-Joe Touma ^{[1
]}

Yassin El-Najjar ^{[1
]}

Alison Colley ^{[2
]}

Daniel J. Boesch ^{[3
]}

Daniel D. Billadeau ^{[4
]}

Jozef Gecz ^{[5
]}

Baoyu Chen ^{[3
]}

Ezra Burstein ^{[1
]}

机构：

[1] University of Texas Southwestern Medical Center,Department of Internal Medicine, Division of Digestive and Liver Diseases

[2] Hunter Genetics,Genetics of Learning Disability Service

[3] Iowa State University,Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology

[4] Mayo Clinic College of Medicine,Division of Oncology Research

[5] University of Adelaide,Neurogenetics Research Program, School of Pediatrics and Reproductive Health

[6] University of Texas Southwestern Medical Center,Department of Molecular Biology

来源：

BMC Medical Genomics | / 18卷 / 1期

关键词：

3 C syndrome; CCDC22; COMMD protein; Retriever; Ritscher-Schinzel syndrome;

D O I：

10.1186/s12920-025-02168-7

中图分类号：

学科分类号：

摘要：

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.

引用