UMMS Affiliation

Program in Molecular Medicine; Biomedical Imaging Group

Date

9-20-2014

Document Type

Article

Disciplines

Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics | Molecular Biology | Molecular Genetics

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 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.

Rights and Permissions

Citation: Orphanet J Rare Dis. 2014 Sep 20;9(1):141. Link to article on publisher's site

DOI of Published Version

10.1186/s13023-014-0141-5

Related Resources

Link to Article in PubMed

Journal Title

Orphanet journal of rare diseases

PubMed ID

25233840

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

 
 

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