Functional characterization of mutations in the myosin Vb gene associated with microvillus inclusion disease

Agata M. Szperl, Magdalena R. Golachowska, Marcel Bruinenberg, Rytis Prekeris, Andy Mark W.H. Thunnissen, Arend Karrenbeld, Gerard Dijkstra, Dick Hoekstra, David Mercer, Janusz Ksiazyk, Cisca Wijmenga, Martin C. Wapenaar, Edmond H.H.M. Rings, Sven C.D. Van Ijzendoorn

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

OBJECTIVES: Microvillus inclusion disease (MVID) is a rare autosomal recessive enteropathy characterized by intractable diarrhea and malabsorption. Recently, various MYO5B gene mutations have been identified in patients with MVID. Interestingly, several patients with MVID showed only a MYO5B mutation in 1 allele (heterozygous) or no mutations in the MYO5B gene, illustrating the need to further functionally characterize the cell biological effects of the MYO5B mutations. PATIENTS AND METHODS: The genomic DNA of 9 patients diagnosed as having MVID was screened for MYO5B mutations, and quantitative polymerase chain reaction and immunohistochemistry on the material of 2 patients was performed to investigate resultant cellular consequences. RESULTS: We demonstrate for the first time that MYO5B mutations can be correlated with altered myosin Vb messenger RNA expression and with an aberrant subcellular distribution of the myosin Vb protein. Moreover, we demonstrate that the typical and myosin Vb-controlled accumulation of Rab11a- and FIP5-positive recycling endosomes in the apical cytoplasm of the cells is abolished in MVID enterocytes, which is indicative of altered myosin Vb function. Moreover, we report 8 novel MYO5B mutations in 9 patients of various ethnic backgrounds with MVID, including compound heterozygous mutations. CONCLUSIONS: Our functional analysis indicates that MYO5B mutations can be correlated with an aberrant subcellular distribution of the myosin Vb protein, and apical recycling endosomes, which, together with the additional compound heterozygous mutations, significantly strengthen the link between MYO5B and MVID.

Original languageEnglish (US)
Pages (from-to)307-313
Number of pages7
JournalJournal of pediatric gastroenterology and nutrition
Volume52
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • apical recycling endosome
  • brush border
  • microvillus inclusion disease
  • myosin Vb

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Gastroenterology

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    Szperl, A. M., Golachowska, M. R., Bruinenberg, M., Prekeris, R., Thunnissen, A. M. W. H., Karrenbeld, A., Dijkstra, G., Hoekstra, D., Mercer, D., Ksiazyk, J., Wijmenga, C., Wapenaar, M. C., Rings, E. H. H. M., & Van Ijzendoorn, S. C. D. (2011). Functional characterization of mutations in the myosin Vb gene associated with microvillus inclusion disease. Journal of pediatric gastroenterology and nutrition, 52(3), 307-313. https://doi.org/10.1097/MPG.0b013e3181eea177