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dc.contributor.authorHofmann, Inga
dc.contributor.authorGeer, Mitchell J
dc.contributor.authorVögtle, Timo
dc.contributor.authorCrispin, Andrew
dc.contributor.authorCampagna, Dean R
dc.contributor.authorBarr, Alastair
dc.contributor.authorCalicchio, Monica L
dc.contributor.authorHeising, Silke
dc.contributor.authorvan Geffen, Johanna P
dc.contributor.authorKuijpers, Marijke JE
dc.contributor.authorHeemskerk, Johan WM
dc.contributor.authorEble, Johannes A
dc.contributor.authorSchmitz-Abe, Klaus
dc.contributor.authorObeng, Esther A
dc.contributor.authorDouglas, Michael
dc.contributor.authorFreson, Kathleen
dc.contributor.authorPondarré, Corinne
dc.contributor.authorFavier, Rémi
dc.contributor.authorJarvis, Gavin
dc.contributor.authorMarkianos, Kyriacos
dc.contributor.authorTurro Bassols, Ernest
dc.contributor.authorOuwehand, Willem
dc.contributor.authorMazharian, Alexandra
dc.contributor.authorFleming, Mark D
dc.contributor.authorSenis, Yotis A
dc.date.accessioned2018-10-10T17:30:52Z
dc.date.available2018-10-10T17:30:52Z
dc.date.issued2018-09-27
dc.identifier.issn0006-4971
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283582
dc.description.abstractUnlike primary myelofibrosis (PMF) in adults, myelofibrosis in children is rare. Congenital (inherited) forms of myelofibrosis (cMF) have been described, but the underlying genetic mechanisms remain elusive. Here we describe 4 families with autosomal recessive inherited macrothrombocytopenia with focal myelofibrosis due to germ line loss-of-function mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B (G6b, C6orf25, or MPIG6B). Patients presented with a mild-to-moderate bleeding diathesis, macrothrombocytopenia, anemia, leukocytosis and atypical megakaryocytes associated with a distinctive, focal, perimegakaryocytic pattern of bone marrow fibrosis. In addition to identifying the responsible gene, the description of G6b-B as the mutated protein potentially implicates aberrant G6b-B megakaryocytic signaling and activation in the pathogenesis of myelofibrosis. Targeted insertion of human G6b in mice rescued the knockout phenotype and a copy number effect of human G6b-B expression was observed. Homozygous knockin mice expressed 25% of human G6b-B and exhibited a marginal reduction in platelet count and mild alterations in platelet function; these phenotypes were more severe in heterozygous mice that expressed only 12% of human G6b-B. This study establishes G6b-B as a critical regulator of platelet homeostasis in humans and mice. In addition, the humanized G6b mouse will provide an invaluable tool for further investigating the physiological functions of human G6b-B as well as testing the efficacy of drugs targeting this receptor.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherAmerican Society of Hematology
dc.subjectBlood Platelets
dc.subjectMegakaryocytes
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectHumans
dc.subjectMice
dc.subjectThrombocytopenia
dc.subjectReceptors, Immunologic
dc.subjectPedigree
dc.subjectAdolescent
dc.subjectAdult
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectInfant
dc.subjectFemale
dc.subjectMale
dc.subjectPrimary Myelofibrosis
dc.subjectYoung Adult
dc.subjectGene Knock-In Techniques
dc.subjectLoss of Function Mutation
dc.titleCongenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice.
dc.typeArticle
prism.endingPage1412
prism.issueIdentifier13
prism.publicationDate2018
prism.publicationNameBlood
prism.startingPage1399
prism.volume132
dc.identifier.doi10.17863/CAM.30944
dcterms.dateAccepted2018-06-05
rioxxterms.versionofrecord10.1182/blood-2017-08-802769
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09
dc.contributor.orcidHofmann, Inga [0000-0001-6125-9655]
dc.contributor.orcidGeer, Mitchell J [0000-0003-1457-987X]
dc.contributor.orcidBarr, Alastair [0000-0001-7738-8419]
dc.contributor.orcidKuijpers, Marijke JE [0000-0001-8987-6532]
dc.contributor.orcidFreson, Kathleen [0000-0002-4381-2442]
dc.contributor.orcidFavier, Rémi [0000-0003-1850-6686]
dc.contributor.orcidJarvis, Gavin [0000-0003-4362-1133]
dc.contributor.orcidMarkianos, Kyriacos [0000-0003-0214-6014]
dc.contributor.orcidTurro Bassols, Ernest [0000-0002-1820-6563]
dc.contributor.orcidOuwehand, Willem [0000-0002-7744-1790]
dc.contributor.orcidMazharian, Alexandra [0000-0002-0204-3325]
dc.contributor.orcidFleming, Mark D [0000-0003-0948-4024]
dc.contributor.orcidSenis, Yotis A [0000-0002-0947-9957]
dc.identifier.eissn1528-0020
rioxxterms.typeJournal Article/Review
pubs.funder-project-idOxford University Hospitals NHS Foundation Trust (unknown)
rioxxterms.freetoread.startdate2019-06-13


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