NIH Research Festival
A ten year old male presenting with joint hypermobility, lens subluxation, elevated hepatic transaminases and generalized lipodystrophy with abnormal body weight was evaluated at the National Institutes of Health Undiagnosed Diseases Program (UDP). Analysis of glycan profiles in the patients’ plasma and primary fibroblasts as well as urine free oligosaccharides revealed an abnormality of N-glycosylation in both plasma and fibroblasts. Exome analysis identified compound heterozygous mutations in the VPS18 gene; a previously unreported variant NM_020857.2:c.205A>G (p.M69V) and a rare SNP NM_020857.2:c.2740C>T (p.R914W). VPS18 is a homologue of the yeast vacuolar sorting protein 18, a class C Vps protein involved in sorting proteins to the late endosome/lysosomes. Human VPS18 has also been shown to have E3 ubiqutin ligase activity. Preliminary analysis of the patient’s fibroblasts indicates a decrease in total lysosomal staining with the vital dye Lysotracker due to fewer lysosomes per cell. Decreased trafficking to the lysosomes could lead to accumulation of aberrantly glycosylated proteins, contributing to the abnormalities detected in the N-glycan profile of this patient. Further characterization of the VPS18 mutant alleles and lysosome function will be discussed.
Scientific Focus Area: Genetics and Genomics
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