A neurodevelopmental disorder caused by mutations in the VPS51 subunit of the GARP and EARP complexes.

Golgi-associated retrograde protein and endosome-associated recycling protein are related heterotetrameric complexes that associate with the cytosolic face of the trans-Golgi network and recycling endosomes, respectively. At these locations, and function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. Gduanyu37 and Eduanyu37 share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. The role of these complexes in human physiology, however, remains poorly understood. By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared subunit VPS51 in a 6-year-old patient with severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features. The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome. In contrast, the other mutant allele produces a protein with a single amino acid substitution that is stable but assembles less efficiently with the other Gduanyu37/Eduanyu37 subunits. Consequently, skin fibroblasts from the patient have reduced levels of fully assembled Gduanyu37 and Eduanyu37 complexes. Likely because of this deficiency, the patient's fibroblasts display altered distribution of the cation-independent mannose 6-phosphate receptor, which normally sorts acid hydrolases to lysosomes. Furthermore, a fraction of the patient's fibroblasts exhibits swelling of lysosomes. These findings thus identify a novel genetic locus for a neurodevelopmental disorder and highlight the critical importance of Gduanyu37/Eduanyu37 function in cellular and organismal physiology.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}