Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex

Mutations in subunits of the SNX17-Retriever-CCC-WASH recycling pathway are involved in human pathologies primarily affecting the nervous system.

“Importantly, a growing body of evidence indicates that mutations in subunits of the SNX17-Retriever-CCC-WASH recycling pathway are involved in human pathologies primarily affecting the nervous system.”

Mutations associated with Ritscher-Schinzel syndrome cause a decrease in the levels of Retriever subunits or CCC subunits, which interferes with the normal function of these complexes.

“several mutations associated with Ritscher-Schinzel syndrome cause a decrease in the levels of Retriever subunits (Otsuji et al., 2022; Kato et al., 2020) or CCC subunits (Starokadomskyy et al., 2013), which interferes with the normal function of these complexes.”

Mutations in Commander subunits are causative for X-linked intellectual disability (XLID) and Ritscher-Schinzel syndrome (RSS).

“mutations in its subunits are causative for X-linked intellectual disability (XLID) and Ritscher-Schinzel syndrome (RSS), a multi-system developmental disorder characterised by abnormal craniofacial features, cerebellar hypoplasia, and stunted cardiovascular development.7,8,9,10,11,12,13,14”

Mutations in Commander lead to hypercholesterolemia through reduced trafficking of LDLRs.

“Mutations in Commander lead to hypercholesterolemia through reduced trafficking of LDLRs.7,8,9,10,12,13,14”

This clustering provides insight into the destabilization of protein expression observed in patients harboring these mutations.

“providing insight into the destabilization of protein expression observed in patients harboring these mutations.8,9,11,12”

Mapping mutations causative for XLID and RSS onto the Commander model reveals clustering of VPS35L and CCDC22 pathogenic mutations around the interface between Retriever and CCC complexes.

“Finally, we mapped mutations causative for XLID and RSS7,8,9,10,11,12 onto the Commander model (Figure 7A). This reveals clustering of VPS35L and CCDC22 pathogenic mutations around the interface between Retriever and CCC complexes”

The structure of the Commander complex has allowed us to map the locations of causative mutations for XLID and RSS.

“The structure of the Commander complex has allowed us to map the locations of causative mutations for XLID and RSS.7,8,9,10,11,12,13,14”

Mutations in WASHC5, CCDC22, and VPS35L result in 3C/Ritscher-Schinzel syndrome.

“Over the past decade, mutations in additional genes, CCDC22 and VPS35L, that also result in 3 C/Ritscher-Schinzel syndrome have been reported [3–7].”

Mutations in WASHC5, CCDC22 and VPS35L all result in hypercholesterolemia in humans, thought to be due to abnormal LDL clearance secondary to defects in LDL receptor recycling.

“It is worth noting that mutations in WASHC5, CCDC22 and VPS35L all result in hypercholesterolemia in humans thought to be due to abnormal LDL clearance secondary to defects in LDL receptor recycling, a phenotype also seen in mouse models of liver deficiency of Ccdc22, Vps35l and Commd1 [5, 7, 30–32].”

The SNX17-Retriever-CCC-WASH sorting pathway controls the sorting and recycling of numerous cell surface proteins, including ITGB1 and LRP1.

“The SNX17-Retriever-CCC-WASH sorting pathway controls the sorting and recycling of numerous cell surface proteins, including integrins, such as integrin β1 (ITGB1), and low-density lipoprotein receptor-related protein 1 (LRP1).”

Depletion of genes in the SNX17-Retriever-CCC-WASH sorting and recycling pathway leads to a decrease in expression of cell surface proteins such as ITGB1 and LRP1.

“As such, depletion of genes in this sorting and recycling pathway leads to a decrease in the expression of these cell surface proteins.”

The previously reported siblings with VPS35L variants comprised an elder girl who died in the infantile period due to sudden cardiac arrest, and a younger boy who presented a variety of severe complications.

“The previously reported siblings with VPS35L variants comprised an elder girl who died in the infantile period due to sudden cardiac arrest, and a younger boy who presented a variety of severe complications.5”