Open Collections

UBC Faculty Research and Publications

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

Abstract

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 > 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. 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.

Item Metadata

Title
Single point mutation in Rabenosyn-5 in a female with intractable seizures and evidence of defective endocytotic trafficking
Creator
Stockler, Sylvia; Corvera, Silvia; Lambright, David; Fogarty, Kevin; Nosova, Ekaterina; Leonard, Deborah; Steinfeld, Robert; Ackerley, Cameron; Shyr, Casper; Au, Nicolas; Selby, Kathrin; van Allen, Margot; Vallance, Hilary; Wevers, Ron; Watkins, David; Rosenblatt, David; Ross, Colin J.; Conibear, Elizabeth; Wasserman, Wyeth W.; van Karnebeek, Clara
Publisher
BioMed Central
Date Issued
2014-09-20
Description
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 > 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. 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.
Subject
Internalization; Receptor endocytosis; Recycling; FYVE domain; Rab GTPase; Epilepsy; Cathepsin D; Vitamin B12; Inborn error of metabolism
Genre
Article
Type
Text
Language
eng
Date Available
2015-11-05
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0215966
URI
http://hdl.handle.net/2429/55212
Affiliation
Medical Genetics, Department of; Medicine, Faculty of; Pathology and Laboratory Medicine, Department of; Pediatrics, Department of; Non UBC
Citation
Orphanet Journal of Rare Diseases. 2014 Sep 20;9(1):141
Publisher DOI
10.1186/s13023-014-0141-5
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
Stockler et al.; licensee BioMed Central Ltd.
Rights URI
http://creativecommons.org/licenses/by/4.0/
Aggregated Source Repository
DSpace

Item Media

Item Citations and Data

Rights

Attribution 4.0 International (CC BY 4.0)