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

Ruemmele, Frank M; Müller, Thomas; Schiefermeier, Natalia; Ebner, Hannes; Lechner, Silvia; Pfaller, Kristian; Thöni, Cornelia E.; Goulet, Olivier; Lacaille, Florence; Schmitz, J; Colomb, V.; Sauvat, Frédérique; Révillon, Y.; Canioni, Danielle; Brousse, Nicole; Basile, Geneviève de Saint; Lefebvre, Juliette M.; Heinz‐Erian, Peter; Enninger, Axel; Utermann, Gerd; Hess, Michael W.; Janecke, Andreas R.; Huber, Lukas A.

doi:10.1002/humu.21224

Cited by 124 publications

(171 citation statements)

References 34 publications

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“…Defective mutations of mammalian MyoV lead to several genetic diseases, such as GS in humans (28) and a similar syndrome in horse MyoVa (29) and microvillus inclusion disease in human MyoVb (30,31). Most of these changes are frame-shift or truncation mutations, which invariably result in truncated proteins lacking all or part of the GTD (Table S2).…”

Section: Resultsmentioning

confidence: 99%

Structural basis of cargo recognitions for class V myosins

Wei

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

101

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Class V myosins (MyoV), the most studied unconventional myosins, recognize numerous cargos mainly via the motor's globular tail domain (GTD). Little is known regarding how MyoV-GTD recognizes such a diverse array of cargos specifically. Here, we solved the crystal structures of MyoVa-GTD in its apo-form and in complex with two distinct cargos, melanophilin and Rab interacting lysosomal protein-like 2. The apo-MyoVa-GTD structure indicates that most mutations found in patients with Griscelli syndrome, microvillus inclusion disease, or cancers or in "dilute" rodents likely impair the folding of GTD. The MyoVa-GTD/cargo complex structure reveals two distinct cargo-binding surfaces, one primarily via charge-charge interaction and the other mainly via hydrophobic interactions. Structural and biochemical analysis reveal the specific cargo-binding specificities of various isoforms of mammalian MyoV as well as very different cargo recognition mechanisms of MyoV between yeast and higher eukaryotes. The MyoVa-GTD structures resolved here provide a framework for future functional studies of vertebrate class V myosins.

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Section: Resultsmentioning

confidence: 99%

Structural basis of cargo recognitions for class V myosins

Wei

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

101

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“…Myo5B-inactivating mutations, either point mutations or truncations, are responsible for the genesis of MVID, which causes severe neonatal diarrhea due to a prominent loss of apical microvilli in intestinal epithelial cells (7,26). Although no mutations in Rab8a been identified in MVID patients, this general intestinal cell phenotype is in part recapitulated in Rab8a knockout mice (27).…”

Section: Discussionmentioning

confidence: 99%

Rab GTPase–Myo5B complexes control membrane recycling and epithelial polarization

Roland

Bryant

Datta

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

181

201

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The Rab GTPases are the largest family of proteins regulating membrane traffic. Rab proteins form a nidus for the assembly of multiprotein complexes on distinct vesicle membranes to regulate particular membrane trafficking pathways. Recent investigations have demonstrated that Myosin Vb (Myo5B) is an effector for Rab8a, Rab10, and Rab11a, all of which are implicated in regulating different pathways for recycling of proteins to the plasma membrane. It remains unclear how specific interactions of Myo5B with individual Rab proteins can lead to specificity in the regulation of alternate trafficking pathways. We examined the relative contributions of Rab/Myo5B interactions with specific pathways using Myo5B mutants lacking binding to either Rab11a or Rab8a. Myo5B Q1300L and Y1307C mutations abolished Rab8a association, whereas Myo5B Y1714E and Q1748R mutations uncoupled association with Rab11a. Expression of Myo5B tails containing these mutants demonstrated that Rab11a, but not Rab8a, was required for recycling of transferrin in nonpolarized cells. In contrast, in polarized epithelial cyst cultures, Myo5B was required for apical membrane trafficking and de novo lumen formation, dependent on association with both Rab8a and Rab11a. These data demonstrate that different combinations of Rab GTPase association with Myo5B control distinct membrane trafficking pathways.

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“…The essential function of microvilli in amplifying surface area is emphasized by the phenotype of patients with MVID, who present with congenital diarrhea in the first days (early-onset form) to months (late-onset) of life (Ruemmele et al, 2010). The defining histological features of MVID are substantial loss of the brush border, presence of intracellular vacuoles with microvilli (microvillus inclusions) and subapical secretory granules in enterocytes (Muller et al, 2008;Ruemmele et al, 2010;Wiegerinck et al, 2014).…”

Section: Microvillus Formation and Absorptive Diseasementioning

confidence: 99%

Generation of intestinal surface: an absorbing tale

et al. 2016

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The vertebrate small intestine requires an enormous surface area to effectively absorb nutrients from food. Morphological adaptations required to establish this extensive surface include generation of an extremely long tube and convolution of the absorptive surface of the tube into villi and microvilli. In this Review, we discuss recent findings regarding the morphogenetic and molecular processes required for intestinal tube elongation and surface convolution, examine shared and unique aspects of these processes in different species, relate these processes to known human maladies that compromise absorptive function and highlight important questions for future research.

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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

Cited by 124 publications

References 34 publications

Structural basis of cargo recognitions for class V myosins

Structural basis of cargo recognitions for class V myosins

Rab GTPase–Myo5B complexes control membrane recycling and epithelial polarization

Generation of intestinal surface: an absorbing tale

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