TY - JOUR
T1 - Functional characterization of mutations in the myosin Vb gene associated with microvillus inclusion disease
AU - Szperl, Agata M.
AU - Golachowska, Magdalena R.
AU - Bruinenberg, Marcel
AU - Prekeris, Rytis
AU - Thunnissen, Andy Mark W.H.
AU - Karrenbeld, Arend
AU - Dijkstra, Gerard
AU - Hoekstra, Dick
AU - Mercer, David
AU - Ksiazyk, Janusz
AU - Wijmenga, Cisca
AU - Wapenaar, Martin C.
AU - Rings, Edmond H.H.M.
AU - Van Ijzendoorn, Sven C.D.
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - apical recycling endosome
KW - brush border
KW - microvillus inclusion disease
KW - myosin Vb
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U2 - 10.1097/MPG.0b013e3181eea177
DO - 10.1097/MPG.0b013e3181eea177
M3 - Article
C2 - 21206382
AN - SCOPUS:79952313074
VL - 52
SP - 307
EP - 313
JO - Journal of Pediatric Gastroenterology and Nutrition
JF - Journal of Pediatric Gastroenterology and Nutrition
SN - 0277-2116
IS - 3
ER -