title: Functional characterization of mutations in the myosin Vb gene associated with microvillus inclusion disease.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Genetics, University Medical Center Groningen, The Netherlands.
authors.forename: Agata M
authors.initials: AM
authors.lastname: Szperl
authors.forename: Magdalena R
authors.initials: MR
authors.lastname: Golachowska
authors.forename: Marcel
authors.initials: M
authors.lastname: Bruinenberg
authors.forename: Rytis
authors.initials: R
authors.lastname: Prekeris
authors.forename: Andy-Mark W H
authors.initials: AM
authors.lastname: Thunnissen
authors.forename: Arend
authors.initials: A
authors.lastname: Karrenbeld
authors.forename: Gerard
authors.initials: G
authors.lastname: Dijkstra
authors.forename: Dick
authors.initials: D
authors.lastname: Hoekstra
authors.forename: David
authors.initials: D
authors.lastname: Mercer
authors.forename: Janusz
authors.initials: J
authors.lastname: Ksiazyk
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Martin C
authors.initials: MC
authors.lastname: Wapenaar
authors.forename: Edmond H H M
authors.initials: EH
authors.lastname: Rings
authors.forename: Sven C D
authors.initials: SC
authors.lastname: van IJzendoorn
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA; D011992:Endosomes / Q000378:metabolism*; D020895:Enterocytes / Q000378:metabolism*; D005260:Female; D016678:Genome; D006579:Heterozygote; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D007223:Infant; D008286:Malabsorption Syndromes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009081:Mucolipidoses / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D024701:Myosin Type V / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D004247:DNA; D024701:Myosin Type V