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

Orphanet Journal of Rare Diseases

Clara van Karnebeek⁹  Wyeth Wasserman⁷  Elizabeth Conibear⁷  Colin J Ross⁹  David Rosenblatt¹  David Watkins¹  Ron Wevers^1,10  Hilary Vallance^1,11  Margot van Allen⁷  Kathrin Selby⁵  Nicolas Au⁴  Casper Shyr⁷  Cameron Ackerley⁶  Robert Steinfeld⁸  Deborah Leonard²  Ekaterina Nosova⁷  Kevin Fogarty²  David Lambright²  Silvia Corvera²  Sylvia Stockler³ 

[1] Department of Human Genetics, McGill University, Montreal, Québec, Canada;Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA;Treatable Intellectual Disability Endeavour in British Columbia, B.C. Children¿s Hospital, Vancouver, Canada;Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, Canada;Division of Pediatric Neurology, B.C. Children¿s Hospital, Vancouver, Canada;Division of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada;Department of Medical Genetics, University of British Columbia, Vancouver, Canada;Department of Pediatrics, University Medical Center Goettingen, Goettingen, Germany;Center for Molecular Medicine and Therapeutics, Child and Family Research Institute, Vancouver, Canada;Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands;Biochemical Genetics Laboratory, Children¿s and Women¿s Hospital, Vancouver, Canada

关键词: Inborn error of metabolism;    Vitamin B12;    Cathepsin D;    Epilepsy;    Rab GTPase;    FYVE domain;    Recycling;    Receptor endocytosis;    Internalization;   

Others  :  1149878
DOI  :  10.1186/s13023-014-0141-5

 received in 2014-04-20, accepted in 2014-08-25,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Stockler et al.; licensee BioMed Central Ltd.

【 图 表 】

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