Program in Molecular Medicine; Biomedical Imaging Group
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics | Molecular Biology | Molecular Genetics
Background. 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.
Methods and results. Whole exome sequencing followed by Sanger sequencing confirmed a rare (frequency:0.003987) homozygous missense mutation, g.15,116,371 G inverted question mark > inverted question markA (c.1273G inverted question mark > inverted question markA), 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 inverted question marks fibroblasts displayed an impaired proliferation rate, cytoskeletal and lysosomal abnormalities.
Conclusion. 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.
DOI of Published Version
Orphanet J Rare Dis. 2014 Sep 20;9(1):141. Link to article on publisher's site
Orphanet journal of rare diseases
Stockler S, Corvera S, Lambright DG, Fogarty KE, Nosova E, Leonard DM, Steinfeld R, Ackerley C, Shyr C, Au N, Selby K, van Allen M, Vallance H, Wevers R, Watkins D, Rosenblatt D, Ross CJ, Conibear E, Wasserman W, van Karnebeek C. (2014). Single point mutation in Rabenosyn-5 in a female with intractable seizures and evidence of defective endocytotic trafficking. Open Access Articles. https://doi.org/10.1186/s13023-014-0141-5. Retrieved from https://escholarship.umassmed.edu/oapubs/2443
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