Singla Amika, Rogers Carolyn, Touma Mary-Joe, El-Najjar Yassin, Colley Alison, Boesch Daniel J, Billadeau Daniel D, Gecz Jozef, Chen Baoyu, Burstein Ezra
Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW, Australia.
BMC Med Genomics. 2025 May 30;18(1):98. doi: 10.1186/s12920-025-02168-7.
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.
CCC复合物由CCDC22、CCDC93和COMMD家族的十种蛋白质组成，它协调内化的质膜蛋白从内体循环到细胞表面所需的几个关键步骤。CCC与Retriever相互作用，Retriever是一种三聚体货物识别复合物，由VPS35L、VPS26C和VPS29组成，并与WASH复合物密切合作，WASH复合物是内体膜上分支肌动蛋白聚合的关键调节因子。编码这三种复合物亚基的基因CCDC22、VPS35L和WASHC5中的突变与一种称为3C（颅-小脑-心脏）或Ritscher-Schinzel综合征的发育综合征有关。在这里，我们报告了一种新的CCDC22错义突变p.E208K，它导致3C综合征症状减轻，且无心脏或神经解剖学异常。我们表明，这种突变通过破坏CCDC22与COMMD4结合所需的保守相互作用表面来损害CCC复合物的组装。我们还回顾了先前描述的病例，发现CCDC22 p.P172R具有类似的减轻表型，并且与p.E208K以类似方式损害复合物组装。这些突变的特征增加了我们对这些疾病临床和分子谱的理解。
