Online Mendelian Inheritance in Man (OMIM) (original) (raw)

Cytogenetic location: 21q22.13 Genomic coordinates (GRCh38) : 21:37,223,420-37,268,108 (from NCBI)

TEXT

Description

The Commander complex is required for endosomal recycling of diverse transmembrane cargoes and consists of 2 subcomplexes: the Retriever complex, which contains VPS35L (618981), VPS26C, and VPS29 (606932), and the CCC complex, which contains the 10 COMMD subunits (see COMMD1, 607238), CCDC22 (300859), and CCDC93 (620553) (summary by Healy et al., 2023).

Cloning and Expression

By GRAIL analysis of a DSCR contig, searching an EST database, and RT-PCR, Nakamura et al. (1997) identified a cDNA encoding DSCR3, which they termed DCRA. The deduced 297-amino acid DSCR3 protein is 92% identical to mouse Dscr3. Northern blot analysis detected a 3.3-kb DSCR3 transcript in fetal brain, heart, lung, liver, and kidney, and adult brain, heart, placenta, lung, liver, skeletal muscle, kidney, and pancreas; a 4-kb transcript was also detected in adult skeletal muscle.

Gene Structure

Nakamura et al. (1997) detected 8 exons in the DCRA gene.

Mapping

Nakamura et al. (1997) identified the DSCR3 gene within the Down syndrome (190685) critical region on chromosome 21q22.2.

Stumpf (2020) mapped the VPS26C gene to chromosome 21q22.13 based on an alignment of the VPS26C sequence (GenBank AK300024) with the genomic sequence (GRCh38).

Gene Function

Using proteomic analysis in human cells, McNally et al. (2017) identified an evolutionarily conserved multiprotein complex that they termed retriever due to its structural and functional similarity with the retromer complex. The retriever complex was a heterodimer composed of DSCR3, C16ORF62 (VPS35L), and VPS29. The retriever complex associated with the CCC and WASH (see 613632) complexes and localized to endosomes to drive retromer-independent retrieval and recycling of numerous cargo proteins by coupling to the cargo adaptor protein SNX17 (605963).

Biochemical Features

Using crystallography, cryoelectron microscopy, and in silico predictions, Healy et al. (2023) assembled a structural model of the complete Commander complex. They found that the trimeric Retriever complex, despite similarity with the Retromer complex, had unique features that mediated its divergent function. In the CCC complex, the 10 COMMD proteins formed a distinctive ring that was stabilized by extensive interactions with CCDC22 and CCDC93. CCDC22 and CCDC93 interacted and formed a heterodimer with 4 coiled-coil regions in 2 V-shaped structures that acted as a linker to connect the Retriever complex to the CCC complex and recruit DENND10 to form the complete Commander complex.

Molecular Genetics

For discussion of a possible association between variation in the VPS26C gene and neurodevelopmental deficits with growth failure and skeletal abnormalities suggestive of Ritscher-Schinzel syndrome (e.g., RTSC1; 220210), see 605298.0001.

ALLELIC VARIANTS 1 Selected Example):

.0001 VARIANT OF UNKNOWN SIGNIFICANCE

VPS26C, GLU60TER
SNP: rs2086074876, ClinVar: RCV001251200, RCV004798896

This variant is classified as a variant of unknown significance because its contribution to a syndrome characterized by neurodevelopmental deficits with growth failure and skeletal abnormalities suggestive of Ritscher-Schinzel syndrome (e.g., RTSC1; 220210) has not been confirmed.

By whole-genome sequencing in 2 cousins from a consanguineous family from the United Arab Emirates with neurodevelopmental deficits with growth failure and skeletal abnormalities and who were negative for mutation in genes associated with known monogenic diseases, Beetz et al. (2020) identified homozygosity for a c.178G-T transversion (c.178G-T, NM_006052) in exon 2 of the VPS26C gene, resulting in a glu60-to-ter (E60X) substitution. The mutation segregated with disease in the family and was not found in the gnomAD or CentoMD databases. Analysis of the proband's heterozygous parents revealed that the abundance of the mutant transcript was approximately 40% of that of wildtype, suggesting incomplete nonsense-mediated mRNA decay. The authors stated that if there is some remaining mutant mRNA, it would likely produce a truncated protein. Collectively, these data were consistent with a loss of function. Functional analysis of the mutant protein was not reported. The cousins, a 13-year-old boy and a 27-year-old woman, shared a pleiotropic disorder with developmental delay and cognitive impairment; short stature with skeletal anomalies, including rhizomelia, brachydactyly, and joint contractures; and distinctive facial features, including severe midface hypoplasia. Photographs of the proband showed dysmorphic clinical features consistent with Ritscher-Schinzel syndrome (Kato et al., 2025).

Kato et al. (2025) demonstrated that knockdown of VPS26C in H4 neuroglioma cells resulted in decreased levels of VPS35L (618981), another components of the Commander complex. VPS26C-null cells showed loss of COMMD1 (607238) endosomal localization and reduced cell surface expression of LRP1 and ITGB1 compared to controls. These findings indicated that loss of VPS26C function results in defects in the SNX17-Retriever/CCC/WASH endosomal cargo retrieval and recycling pathway, similar to other forms of RTSC.

REFERENCES

  1. Beetz, C., Ameziane, N., Kdissa, A., Karageorgou, V., Bauer, P., Suleiman, J., Sutton, V. R., El-Hattab, A. W.VPS26C homozygous nonsense variant in two cousins with neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features. Clin. Genet. 97: 644-648, 2020. [PubMed: 31845315] [Full Text: https://doi.org/10.1111/cge.13690\]
  2. Healy, M. D., McNally, K. E., Butkovic, R., Chilton, M., Kato, K., Sacharz, J., McConville, C., Moody, E. R. R., Shaw, S., Planelles-Herrero, V. J., Yadav, S. K. N., Ross, J., and 17 others.Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome. Cell 186: 2219-2237, 2023. [PubMed: 37172566] [Full Text: https://doi.org/10.1016/j.cell.2023.04.003\]
  3. Kato, K., Nishio, Y., McMillan, K. J., Al-Maraghi, A., Kroes, H. Y., Abdel-Hamid, M. S., Jones, E., Shaw, S., Yoshida, A., Otsuji, S., Murofushi, Y., Aamer, W., and 27 others.Ritscher-Schinzel syndrome can be characterized as an endosomal recyclinopathy. Sci. Transl. Med. 17: eadt2426, 2025. [PubMed: 40601774] [Full Text: https://doi.org/10.1126/scitranslmed.adt2426\]
  4. McNally, K. E., Faulkner, R., Steinberg, F., Gallon, M., Ghai, R., Pim, D., Langton, P., Pearson, N., Danson, C. M., Nagele, H., Morris, L. L., Singla, A., and 9 others.Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nature Cell Biol. 19: 1214-1225, 2017. [PubMed: 28892079] [Full Text: https://doi.org/10.1038/ncb3610\]
  5. Nakamura, A., Hattori, M., Sakaki, Y.Isolation of a novel human gene from the Down syndrome critical region of chromosome 21q22.2. J. Biochem. 122: 872-877, 1997. [PubMed: 9399594] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a021835\]
  6. Stumpf, A. M.Personal Communication. Baltimore, Md. 08/05/2020.