Single point mutation in Rabenosyn-5 in a female with intractable seizures and evidence of defective endocytotic trafficking.

Orphanet journal of rare diseases 2014 Sep 20

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We report a 6.5 year-old female with a homozygous missense mutation in ZFYVE20, encoding Rabenosyn-5 (Rbsn-5), a highly conserved multi-domain protein implicated in receptor-mediated endocytosis. The clinical presentation includes intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis. Biochemical findings include transient cobalamin deficiency, severe hypertriglyceridemia upon ketogenic diet, microalbuminuria and partial cathepsin D deficiency. Whole exome sequencing followed by Sanger sequencing confirmed a rare (frequency:0.003987) homozygous missense mutation, g.15,116,371 G > A (c.1273G > A), in ZFYVE20 resulting in an amino acid change from Glycine to Arginine at position 425 of the Rbsn protein (p.Gly425Arg), as the only mutation segregating with disease in the family. Studies in fibroblasts revealed expression and localization of Rbsn-5G425R in wild-type manner, but a 50% decrease in transferrin accumulation, which is corrected by wild-type allele transfection. Furthermore, the patient's fibroblasts displayed an impaired proliferation rate, cytoskeletal and lysosomal abnormalities. These results are consistent with a functional defect in the early endocytic pathway resulting from mutation in Rbsn-5, which secondarily disrupts multiple cellular functions dependent on endocytosis, leading to a severe multi-organ disorder.

Citation

Sylvia Stockler, Silvia Corvera, David Lambright, Kevin Fogarty, Ekaterina Nosova, Deborah Leonard, Robert Steinfeld, Cameron Ackerley, Casper Shyr, Nicolas Au, Kathrin Selby, Margot van Allen, Hilary Vallance, Ron Wevers, David Watkins, David Rosenblatt, Colin J Ross, Elizabeth Conibear, Wyeth Wasserman, Clara van Karnebeek. Single point mutation in Rabenosyn-5 in a female with intractable seizures and evidence of defective endocytotic trafficking. Orphanet journal of rare diseases. 2014 Sep 20;9:141