Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.

1st Department of Pediatrics Athens University Medical School 11527 Athens Greece

Aghia Sofia Children's Hospital Neonatal Intensive Care Unit B 115 27 Athens Greece

Ankara Child Health and Diseases Training and Research Hospital Neonatology 06120 Ankara Turkey

Ankara Child Health and Diseases Training and Research Hospital Pediatric Gastroenterology 06130 Ankara Turkey

Assistance Publique Hôpitaux de Paris Hôpital Universitaire Necker Enfants Malades Service de Gastroentérologie Hépatologie et Nutrition Pédiatrique 149 Rue de Sèvres 75015 Paris France

Austrian Drug Screening Institute ADSI 6020 Innsbruck Austria

Children's Hospital Tübingen 72076 Tübingen Germany

Department for Pediatric Gastroenterology and Hepatology University Children's Hospital Bonn 53127 Bonn Germany

Department for Pediatric Nephrology Gastroenterology Endocrinology and Transplant Medicine Clinic for Pediatrics 2 University Children's Hospital Essen University Duisburg Essen 45147 Essen Germany

Department of Medical Genetics Kepler University Hospital School of Medicine Johannes Kepler University A 4020 Linz Austria

Department of Neonatology Johannes Kepler University Linz A 4020 Linz Austria

Department of Paediatric Gastroenterology Unit of Nutrition and Intestinal Failure Rehabilitation Great Ormond Street Hospital for Sick Children NHS Foundation Trust Great Ormond Street London WC1N 3JH UK

Department of Paediatrics and Adolescent Medicine Johannes Kepler University Linz A 4020 Linz Austria

Department of Paediatrics Helios Medical Centre Wuppertal Witten Herdecke University 58455 Witten Germany

Department of Pediatric Gastroenterology Hepatology and Nutrition Health Science University Sadi Konuk Education and Research Hospital 34147 Istanbul Turkey

Department of Pediatric Sheikh Khalifa Medical City College of Medicine and Health Sciences Khalife University Abu Dhabi 127788 United Arab Emirates

Department of Pediatrics 1 Medical University of Innsbruck A 6020 Innsbruck Austria

Department of Pediatrics and Adolescent Medicine Faculty of Medicine Medical Center University of Freiburg 79106 Freiburg Germany

Department of Pediatrics and Adolescent Medicine University Medical Center Ulm Eythstr 24 89075 Ulm Germany

Department of Pediatrics Faculty of Medicine Comenius University National Institute of Children Diseases 814 99 Bratislava Slovakia

Department of Pediatrics University of Oxford Oxford OX3 9DU UK

Departments of Pediatric Gastroenterology Hepatology and Nutrition Faculty of Medicine Karadeniz Technical University 61080 Trabzon Turkey

Division of Cell Biology Biocenter Innsbruck Medical University A 6020 Innsbruck Austria

Division of Cell Biology Medical University of Innsbruck A 6020 Innsbruck Austria

Division of Gastroenterology Hepatology and Nutrition The Hospital for Sick Children Toronto ON M5G 0A4 Canada

Division of Human Genetics Medical University of Innsbruck A 6020 Innsbruck Austria

Emma Children's Hospital AMC 1105 Amsterdam The Netherlands

Genetics Metabolics Service Tawam Hospital Al Ain 15258 United Arab Emirates

Hospital Universitario San Vicente de Paúl Medellín Antioquia 50022 Colombia

Institute of Histology and Embryology Medical University of Innsbruck A 6020 Innsbruck Austria

Intestinal Rehabilitation Unit Pediatric Gastroenterology and Nutrition Unit University Hospital La Paz 28046 Madrid Spain

Paediatrics at the Medical Faculty Université de Paris 75005 Paris France

Pediatric Gastroenterology Department of Pediatrics Faculty of Medicine in Hradec Králové Charles University 110 00 Prague Czech Republic

Pediatric Gastroenterology Shaare Zedek Medical Center 9103102 Jerusalem Israel

SW Thames Regional Genetics Service St George's University NHS Foundation Trust London SW17 0QT UK

Translational Gastroenterology Unit University of Oxford Oxford OX3 9DU UK

Unidade de Gastrenterologia Pediátrica Centro Hospitalar do Porto 4099 001 Porto Portugal

Universitätsklinik für Kinder und Jugendmedizin Tübingen Pädiatrische Gastroenterologie und Hepatologie Hoppe Seyler Straße 1 72076 Tübingen Germany

University of Health Sciences Sami Ulus Maternity and Child Health and Diseases Training and Research Hospital 06120 Ankara Turkey

See more in PubMed

Vogel G.F., Janecke A.R., Krainer I.M., Gutleben K., Witting B., Mitton S.G., Mansour S., Ballauff A., Roland J.T., Engevik A.C., et al. Abnormal Rab11-Rab8-vesicles cluster in enterocytes of patients with microvillus inclusion disease. Traffic. 2017;18:453–464. doi: 10.1111/tra.12486. PubMed DOI PMC

Davidson G.P., Cutz E., Hamilton J.R., Gall D.G. Familial enteropathy: A syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villus atrophy. Gastroenterology. 1978;75:783–790. doi: 10.1016/0016-5085(78)90458-4. PubMed DOI

Cutz E., Rhoads J.M., Drumm B., Sherman P.M., Durie P.R., Forstner G.G. Microvillus inclusion disease: An inherited defect of brush-border assembly and differentiation. N. Engl. J. Med. 1989;320:646–651. doi: 10.1056/NEJM198903093201006. PubMed DOI

Ruemmele F.M., Schmitz J., Goulet O. Microvillous inclusion disease (microvillous atrophy) Orphanet J. Rare Dis. 2006;1:22. doi: 10.1186/1750-1172-1-22. PubMed DOI PMC

Wiegerinck C.L., Janecke A.R., Schneeberger K., Vogel G.F., van Haaften-Visser D.Y., Escher J.C., Adam R., Thoni C.E., Pfaller K., Jordan A.J., et al. Loss of syntaxin 3 causes variant microvillus inclusion disease. Gastroenterology. 2014;147:65–68. doi: 10.1053/j.gastro.2014.04.002. PubMed DOI

Stepensky P., Bartram J., Barth T.F., Lehmberg K., Walther P., Amann K., Philips A.D., Beringer O., Zur Stadt U., Schulz A., et al. Persistent defective membrane trafficking in epithelial cells of patients with familial hemophagocytic lymphohistiocytosis type 5 due to STXBP2/MUNC18-2 mutations. Pediatr. Blood Cancer. 2013;60:1215–1222. doi: 10.1002/pbc.24475. PubMed DOI

Dhekne H.S., Pylypenko O., Overeem A.W., Ferreira R.J., van der Velde K.J., Rings E., Posovszky C., Swertz M.A., Houdusse A., van IJzendoorn S.C.D. MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update. Hum. Mutat. 2018;39:333–344. doi: 10.1002/humu.23386. PubMed DOI PMC

Vogel G.F., van Rijn J.M., Krainer I.M., Janecke A.R., Posovszky C., Cohen M., Searle C., Jantchou P., Escher J.C., Patey N., et al. Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations. JCI Insight. 2017;2 doi: 10.1172/jci.insight.94564. PubMed DOI PMC

Girard M., Lacaille F., Verkarre V., Mategot R., Feldmann G., Grodet A., Sauvat F., Irtan S., Davit-Spraul A., Jacquemin E., et al. MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease. Hepatology. 2014;60:301–310. doi: 10.1002/hep.26974. PubMed DOI

Gonzales E., Taylor S.A., Davit-Spraul A., Thebaut A., Thomassin N., Guettier C., Whitington P.F., Jacquemin E. MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease. Hepatology. 2017;65:164–173. doi: 10.1002/hep.28779. PubMed DOI

Qiu Y.L., Gong J.Y., Feng J.Y., Wang R.X., Han J., Liu T., Lu Y., Li L.T., Zhang M.H., Sheps J.A., et al. Defects in myosin VB are associated with a spectrum of previously undiagnosed low gamma-glutamyltransferase cholestasis. Hepatology. 2017;65:1655–1669. doi: 10.1002/hep.29020. PubMed DOI PMC

Bull L.N., Carlton V.E., Stricker N.L., Baharloo S., DeYoung J.A., Freimer N.B., Magid M.S., Kahn E., Markowitz J., DiCarlo F.J., et al. Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): Evidence for heterogeneity. Hepatology. 1997;26:155–164. doi: 10.1002/hep.510260121. PubMed DOI

Sambrotta M., Strautnieks S., Papouli E., Rushton P., Clark B.E., Parry D.A., Logan C.V., Newbury L.J., Kamath B.M., Ling S., et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nat. Genet. 2014;46:326–328. doi: 10.1038/ng.2918. PubMed DOI PMC

Droge C., Bonus M., Baumann U., Klindt C., Lainka E., Kathemann S., Brinkert F., Grabhorn E., Pfister E.D., Wenning D., et al. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. J. Hepatol. 2017;67:1253–1264. doi: 10.1016/j.jhep.2017.07.004. PubMed DOI

Overeem A.W., Li Q., Qiu Y.L., Carton-Garcia F., Leng C., Klappe K., Dronkers J., Hsiao N.H., Wang J.S., Arango D., et al. A Molecular Mechanism Underlying Genotype-Specific Intrahepatic Cholestasis Resulting From MYO5B Mutations. Hepatology. 2020;72:213–229. doi: 10.1002/hep.31002. PubMed DOI PMC

van der Velde K.J., Dhekne H.S., Swertz M.A., Sirigu S., Ropars V., Vinke P.C., Rengaw T., van den Akker P.C., Rings E.H., Houdusse A., et al. An overview and online registry of microvillus inclusion disease patients and their MYO5B mutations. Hum. Mutat. 2013;34:1597–1605. doi: 10.1002/humu.22440. PubMed DOI

Muller T., Hess M.W., Schiefermeier N., Pfaller K., Ebner H.L., Heinz-Erian P., Ponstingl H., Partsch J., Rollinghoff B., Kohler H., et al. MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat. Genet. 2008;40:1163–1165. doi: 10.1038/ng.225. PubMed DOI

Ruemmele F.M., Muller T., Schiefermeier N., Ebner H.L., Lechner S., Pfaller K., Thoni C.E., Goulet O., Lacaille F., Schmitz J., et al. Loss-of-function of MYO5B is the main cause of microvillus inclusion disease: 15 novel mutations and a CaCo-2 RNAi cell model. Hum. Mutat. 2010;31:544–551. doi: 10.1002/humu.21224. PubMed DOI

Klee K.M.C., Janecke A.R., Civan H.A., Rosipal S., Heinz-Erian P., Huber L.A., Muller T., Vogel G.F. AP1S1 missense mutations cause a congenital enteropathy via an epithelial barrier defect. Hum. Genet. 2020;139:1247–1259. doi: 10.1007/s00439-020-02168-w. PubMed DOI PMC

Ghosh R., Oak N., Plon S.E. Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines. Genome Biol. 2017;18:225. doi: 10.1186/s13059-017-1353-5. PubMed DOI PMC

van IJzendoorn S.C.D., Li Q., Qiu Y.L., Wang J.S., Overeem A.W. Unequal effects of MYO5B mutations in liver and intestine determine the clinical presentation of low-GGT cholestasis. Hepatology. 2020 doi: 10.1002/hep.31430. PubMed DOI PMC

Schneeberger K., Vogel G.F., Teunissen H., van Ommen D.D., Begthel H., El Bouazzaoui L., van Vugt A.H., Beekman J.M., Klumperman J., Muller T., et al. An inducible mouse model for microvillus inclusion disease reveals a role for myosin Vb in apical and basolateral trafficking. Proc. Natl. Acad. Sci. USA. 2015;112:12408–12413. doi: 10.1073/pnas.1516672112. PubMed DOI PMC

Szperl A.M., Golachowska M.R., Bruinenberg M., Prekeris R., Thunnissen A.M., Karrenbeld A., Dijkstra G., Hoekstra D., Mercer D., Ksiazyk J., et al. Functional characterization of mutations in the myosin Vb gene associated with microvillus inclusion disease. J. Pediatr. Gastroenterol. Nutr. 2011;52:307–313. doi: 10.1097/MPG.0b013e3181eea177. PubMed DOI PMC

Golachowska M.R., van Dael C.M., Keuning H., Karrenbeld A., Hoekstra D., Gijsbers C.F., Benninga M.A., Rings E.H., van Ijzendoorn S.C. MYO5B mutations in patients with microvillus inclusion disease presenting with transient renal Fanconi syndrome. J. Pediatr. Gastroenterol. Nutr. 2012;54:491–498. doi: 10.1097/MPG.0b013e3182353773. PubMed DOI

Erickson R.P., Larson-Thome K., Valenzuela R.K., Whitaker S.E., Shub M.D. Navajo microvillous inclusion disease is due to a mutation in MYO5B. Am. J. Med. Genet. A. 2008;146A:3117–3119. doi: 10.1002/ajmg.a.32605. PubMed DOI

Cockar I., Foskett P., Strautnieks S., Clinch Y., Fustok J., Rahman O., Sutton H., Mtegha M., Fessatou S., Kontaki E., et al. Mutations in Myosin 5B in Children With Early-onset Cholestasis. J. Pediatr. Gastroenterol. Nutr. 2020;71:184–188. doi: 10.1097/MPG.0000000000002740. PubMed DOI

Comegna M., Amato F., Liguori R., Berni Canani R., Spagnuolo M.I., Morroni M., Guarino A., Castaldo G. Two cases of microvillous inclusion disease caused by novel mutations in MYO5B gene. Clin. Case Rep. 2018;6:2451–2456. doi: 10.1002/ccr3.1879. PubMed DOI PMC

Perry A., Bensallah H., Martinez-Vinson C., Berrebi D., Arbeille B., Salomon J., Goulet O., Marinier E., Drunat S., Samson-Bouma M.E., et al. Microvillous atrophy: Atypical presentations. J. Pediatr. Gastroenterol. Nutr. 2014;59:779–785. doi: 10.1097/MPG.0000000000000526. PubMed DOI

Chen C.P., Chiang M.C., Wang T.H., Hsueh C., Chang S.D., Tsai F.J., Wang C.N., Chern S.R., Wang W. Microvillus inclusion disease: Prenatal ultrasound findings, molecular diagnosis and genetic counseling of congenital diarrhea. Taiwan. J. Obstet. Gynecol. 2010;49:487–494. doi: 10.1016/S1028-4559(10)60102-7. PubMed DOI

Mao M., Guo L., Zhang Z., Wang B., Huang S., Song Y., Chen F., Wen W. Phenotypic and genetic analysis of a family affected with microvillus inclusion disease. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2016;33:792–796. doi: 10.3760/cma.j.issn.1003-9406.2016.06.010. PubMed DOI

Fernandez Caamano B., Quiles Blanco M.J., Fernandez Tome L., Burgos Lizaldez E., Sarria Oses J., Molina Arias M., Prieto Bozano G. Intestinal failure and transplantation in microvillous inclusion disease. An. Pediatr. (Barc.) 2015;83:160–165. doi: 10.1016/j.anpede.2015.08.001. PubMed DOI

Croft N.M., Howatson A.G., Ling S.C., Nairn L., Evans T.J., Weaver L.T. Microvillous inclusion disease: An evolving condition. J. Pediatr. Gastroenterol. Nutr. 2000;31:185–189. doi: 10.1097/00005176-200008000-00019. PubMed DOI

Sadiq M., Choudry O., Kashyap A., Velazquez D.M. Congenital diarrhea in a newborn infant: A case report. World J. Clin. Pediatr. 2019;8:43–48. doi: 10.5409/wjcp.v8.i3.43. PubMed DOI PMC

Thiagarajah J.R., Kamin D.S., Acra S., Goldsmith J.D., Roland J.T., Lencer W.I., Muise A.M., Goldenring J.R., Avitzur Y., Martin M.G., et al. Advances in Evaluation of Chronic Diarrhea in Infants. Gastroenterology. 2018;154:2045–2059.e6. doi: 10.1053/j.gastro.2018.03.067. PubMed DOI PMC

Goulet O., Ruemmele F. Causes and management of intestinal failure in children. Gastroenterology. 2006;130:S16–S28. doi: 10.1053/j.gastro.2005.12.002. PubMed DOI

Vogel G.F., Klee K.M., Janecke A.R., Muller T., Hess M.W., Huber L.A. Cargo-selective apical exocytosis in epithelial cells is conducted by Myo5B, Slp4a, Vamp7, and Syntaxin 3. J. Cell Biol. 2015;211:587–604. doi: 10.1083/jcb.201506112. PubMed DOI PMC

Schlegel C., Weis V.G., Knowles B.C., Lapierre L.A., Martin M.G., Dickman P., Goldenring J.R., Shub M.D. Apical Membrane Alterations in Non-intestinal Organs in Microvillus Inclusion Disease. Dig. Dis. Sci. 2018;63:356–365. doi: 10.1007/s10620-017-4867-5. PubMed DOI PMC

Roland J.T., Bryant D.M., Datta A., Itzen A., Mostov K.E., Goldenring J.R. Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization. Proc. Natl. Acad. Sci. USA. 2011;108:2789–2794. doi: 10.1073/pnas.1010754108. PubMed DOI PMC

Ridlon J.M., Kang D.J., Hylemon P.B., Bajaj J.S. Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 2014;30:332–338. doi: 10.1097/MOG.0000000000000057. PubMed DOI PMC

Carton-Garcia F., Overeem A.W., Nieto R., Bazzocco S., Dopeso H., Macaya I., Bilic J., Landolfi S., Hernandez-Losa J., Schwartz S., Jr., et al. Myo5b knockout mice as a model of microvillus inclusion disease. Sci. Rep. 2015;5:12312. doi: 10.1038/srep12312. PubMed DOI PMC

Weis V.G., Knowles B.C., Choi E., Goldstein A.E., Williams J.A., Manning E.H., Roland J.T., Lapierre L.A., Goldenring J.R. Loss of MYO5B in mice recapitulates Microvillus Inclusion Disease and reveals an apical trafficking pathway distinct to neonatal duodenum. Cell. Mol. Gastroenterol. Hepatol. 2016;2:131–157. doi: 10.1016/j.jcmgh.2015.11.009. PubMed DOI PMC