MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity

Müller, Thomas; Hess, Michael W.; Schiefermeier, Natalia; Pfaller, Kristian; Ebner, Hannes; Heinz‐Erian, Peter; Ponstingl, Hannes; Partsch, Joachim; Röllinghoff, Barbara; Köhler, Henrik; Berger, Thomas; Lenhartz, Henning; Schlenck, Barbara; Houwen, Roderick J; Taylor, Christopher J.; Zoller, Heinz; Lechner, Silvia; Goulet, Olivier; Utermann, Gerd; Ruemmele, Frank M; Huber, Lukas A.; Janecke, Andreas R.

doi:10.1038/ng.225

Cited by 322 publications

(340 citation statements)

References 15 publications

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“…The MYO5B coding region and splice sites (GenBank reference sequence NM_001080467.1) were PCR-amplified and directly sequenced in all patient samples as described previously [Muller et al, 2008]. The sequencing reactions were analyzed on an ABI 3100 DNA sequencer, with BigDye terminator mix (Applied Biosystems, Vienna, Austria).…”

Section: Mutation Analysismentioning

confidence: 99%

“…Recently, we have shown that mutations in MYO5B (MIM] 606540), encoding the unconventional type Vb myosin motor protein, are associated with MVID in a first small cohort of patients with earlyonset MVID, firmly establishing autosomal recessive inheritance of MVID [Muller et al, 2008]. MYO5B mutations were associated with disrupted epithelial cell polarity implicating MYO5B in the regulation of intracellular protein trafficking [Muller et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

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Loss-of-function of MYO5B is the main cause of microvillus inclusion disease: 15 novel mutations and a CaCo-2 RNAi cell model

et al. 2010

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Autosomal recessive microvillus inclusion disease (MVID) is characterized by an intractable diarrhea starting within the first few weeks of life. The hallmarks of MVID are a lack of microvilli on the surface of villous enterocytes, occurrence of intracellular vacuoles lined by microvilli (microvillus inclusions), and the cytoplasmic accumulation of periodic acid-Schiff (PAS)-positive vesicles in enterocytes. Recently, we identified mutations in MYO5B, encoding the unconventional type Vb myosin motor protein, in a first cohort of nine MVID patients. In this study, we identified 15 novel nonsense and missense mutations in MYO5B in 11 unrelated MVID patients. Fluorescence microscopy, Western blotting, and electron microscopy were applied to analyze the effects of MYO5B siRNA knockdown in polarized, brush border possessing CaCo-2 cells. Loss of surface microvilli, increased formation of microvillus inclusions, and subapical enrichment of PAS-positive endomembrane compartments were induced in polarized, filter-grown CaCo-2 cells, following MYO5B knock-down. Our data indicate that MYO5B mutations are a major cause of microvillus inclusion disease and that MYO5B knockdown recapitulates most of the cellular phenotype in vitro, thus independently showing loss of MYO5B function as the cause of microvillus inclusion disease.

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Section: Mutation Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss-of-function of MYO5B is the main cause of microvillus inclusion disease: 15 novel mutations and a CaCo-2 RNAi cell model

et al. 2010

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“…Recent studies identified mutations in the MYO5B gene as a cause of most cases of MVID. 6,10,12 The loss of the MYO5B gene expression leads to defective cellular traffic and disrupted cell polarity of enterocytes. 6,10,18 Mutation in the syntaxin3 gene has been described recently in a case of variant form of MVID, presenting with milder clinical symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…6,10,12 The loss of the MYO5B gene expression leads to defective cellular traffic and disrupted cell polarity of enterocytes. 6,10,18 Mutation in the syntaxin3 gene has been described recently in a case of variant form of MVID, presenting with milder clinical symptoms. 19 We also show expression of cell adhesion molecules beta-catenin and EpCAM as well as an ion pump Na/K ATPase to the basolateral membrane of normal enterocytes.…”

Section: Discussionmentioning

confidence: 99%

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Multilabel immunofluorescence and antigen reprobing on formalin-fixed paraffin-embedded sections: novel applications for precision pathology diagnosis

et al. 2016

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We report new methods for multilabel immunofluorescence (MIF) and reprobing of antigen epitopes on the same formalin-fixed paraffin-embedded (FFPE) sections. The MIF method includes an antigen-retrieval step followed by multilabel immunostaining and examination by confocal microscopy. As examples, we illustrate epitopes localized to the apical and basolateral membranes, and the cytoplasm of enterocytes of normal small intestine and in cases of congenital enteropathies (microvillous inclusion disease and congenital tufting enteropathy). We also demonstrate localization of the bile salt excretion pump protein (BSEP) in bile canalicular membrane of normal hepatocytes and in cases of primary sclerosing cholangitis. To demonstrate colocalization of cytoplasmic and nuclear epitopes we analyzed normal control and hyperplastic pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEBs), presumed airway sensors in the lungs of infants with bronchopulmonary dysplasia (BPD). As cytoplasmic markers we used anti-bombesin or anti-synaptic vesicle protein 2 (SV2) antibody, respectively, and for nuclear localization, antibodies against neurogenic genes mammalian achaete-scute homolog (Mash1) and prospero homeobox 1 (Prox1), essential for NEB cells differentiation and maturation, hypoxia-inducible factor 1α (HIF1α) a downstream modulator of hypoxia response and a proliferation marker Ki67. The reprobing method consisted of removal of the previously immunolabeled target and immunostaining with different antibodies, facilitating colocalization of enterocyte brush border epitopes as well as HIF1α, Mash1 and Prox1 in PNEC/NEB PNEC and NEBs. As these methods are suitable for routine FFPE pathology samples from various tissues, allowing visualization of multiple epitopes in the same cells/sections with superior contrast and resolution, they are suitable for a wide range of applications in diagnostic pathology and may be particularly well suited for precision medicine diagnostics.

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Apical Recycling of Canalicular ABC Transporters

Wakabayashi

Arias

2009

The Liver

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MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity

Cited by 322 publications

References 15 publications

Loss-of-function of MYO5B is the main cause of microvillus inclusion disease: 15 novel mutations and a CaCo-2 RNAi cell model

Loss-of-function of MYO5B is the main cause of microvillus inclusion disease: 15 novel mutations and a CaCo-2 RNAi cell model

Multilabel immunofluorescence and antigen reprobing on formalin-fixed paraffin-embedded sections: novel applications for precision pathology diagnosis

Apical Recycling of Canalicular ABC Transporters

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