title: Single point mutation in Rabenosyn-5 in a female with intractable seizures and evidence of defective endocytotic trafficking.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler
authors.forename: Silvia
authors.initials: S
authors.lastname: Corvera
authors.forename: David
authors.initials: D
authors.lastname: Lambright
authors.forename: Kevin
authors.initials: K
authors.lastname: Fogarty
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Nosova
authors.forename: Deborah
authors.initials: D
authors.lastname: Leonard
authors.forename: Robert
authors.initials: R
authors.lastname: Steinfeld
authors.forename: Cameron
authors.initials: C
authors.lastname: Ackerley
authors.forename: Casper
authors.initials: C
authors.lastname: Shyr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Au
authors.forename: Kathrin
authors.initials: K
authors.lastname: Selby
authors.forename: Margot
authors.initials: M
authors.lastname: van Allen
authors.forename: Hilary
authors.initials: H
authors.lastname: Vallance
authors.forename: Ron
authors.initials: R
authors.lastname: Wevers
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.forename: David
authors.initials: D
authors.lastname: Rosenblatt
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Conibear
authors.forename: Wyeth
authors.initials: W
authors.lastname: Wasserman
authors.forename: Clara
authors.initials: C
authors.lastname: van Karnebeek
mesh_terms: D002648:Child; D004705:Endocytosis / Q000235:genetics*; D005260:Female; D006801:Humans; D017354:Point Mutation / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D012640:Seizures / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C416362:RBSN protein, human; D033921:Vesicular Transport Proteins