Background: Vacuolar protein sorting-associated protein 52 (VPS52) is a core protein subunit of both the Golgi-associated retrograde protein (GARP) and the endosome-associated recycling protein (EARP) complexes. Both are heterotetramers involved in the intracellular vesicle trafficking network in eukaryote cells.
Aim: Confirm the pathogenicity of variants identified in VPS52 as a novel disease gene.
Methods: Exome sequencing was followed by both molecular and zebrafish model experiments, which explored the pathogenicity of hypomorphic loss-of-function variants in VPS52.
Results: Through exome sequencing, we discovered two affected sibs in a New Zealand family are compound heterozygous for variants in VPS52. Both affected sibs have microcephaly, seizures and developmental delay. Through international collaborations via Genematcher, we have identified seven families with biallelic variants, including four families from Saudi Arabia segregating the same missense variant. Affected cases have neurological and non-neurological abnormalities, ranging from ventriculomegaly to microcephaly with arthrogryposis and cholestasis. Through studying patient fibroblasts and reporter cell models, we confirmed that variants act in a loss-of-function manner to reduce VPS52 transcript or protein levels, with a subsequent cellular effect on complex stability, lysosomal levels and lysosomal localisation in the cell. Genome editing targeting vps52 in a zebrafish model confirmed similar developmental effects.
Conclusion: We have identified that VPS52 is a novel disease gene, where biallelic variants act through a loss-of-function mechanism to disrupt intracellular trafficking. Our findings add further insight into the consequences of impaired vesicle trafficking and the importance of this cellular function in brain development.