Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature
Identifieur interne : 002C69 ( Pmc/Corpus ); précédent : 002C68; suivant : 002C70Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature
Auteurs : Jan Kazenwadel ; Genevieve A. Secker ; Yajuan J. Liu ; Jill A. Rosenfeld ; Robert S. Wildin ; Jennifer Cuellar-Rodriguez ; Amy P. Hsu ; Sarah Dyack ; Conrad V. Fernandez ; Chan-Eng Chong ; Milena Babic ; Peter G. Bardy ; Akiko Shimamura ; Michael Y. Zhang ; Tom Walsh ; Steven M. Holland ; Dennis D. Hickstein ; Marshall S. Horwitz ; Christopher N. Hahn ; Hamish S. Scott ; Natasha L. HarveySource :
- Blood [ 0006-4971 ] ; 2012.
Abstract
Recent work has established that heterozygous germline
Url:
DOI: 10.1182/blood-2011-08-374363
PubMed: 22147895
PubMed Central: 3277359
Links to Exploration step
PMC:3277359Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Loss-of-function germline <italic>GATA2</italic>
mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature</title>
<author><name sortKey="Kazenwadel, Jan" sort="Kazenwadel, Jan" uniqKey="Kazenwadel J" first="Jan" last="Kazenwadel">Jan Kazenwadel</name>
<affiliation><nlm:aff id="aff1">Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Secker, Genevieve A" sort="Secker, Genevieve A" uniqKey="Secker G" first="Genevieve A." last="Secker">Genevieve A. Secker</name>
<affiliation><nlm:aff id="aff1">Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Liu, Yajuan J" sort="Liu, Yajuan J" uniqKey="Liu Y" first="Yajuan J." last="Liu">Yajuan J. Liu</name>
<affiliation><nlm:aff id="aff2">Department of Pathology, University of Washington School of Medicine, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rosenfeld, Jill A" sort="Rosenfeld, Jill A" uniqKey="Rosenfeld J" first="Jill A." last="Rosenfeld">Jill A. Rosenfeld</name>
<affiliation><nlm:aff id="aff3">Signature Genomics, PerkinElmer, Spokane, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wildin, Robert S" sort="Wildin, Robert S" uniqKey="Wildin R" first="Robert S." last="Wildin">Robert S. Wildin</name>
<affiliation><nlm:aff id="aff4">St Luke's Children's Hospital, Pediatric Genetics, and State of Idaho Genetics Program, Department of Health and Welfare, Boise, ID;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cuellar Rodriguez, Jennifer" sort="Cuellar Rodriguez, Jennifer" uniqKey="Cuellar Rodriguez J" first="Jennifer" last="Cuellar-Rodriguez">Jennifer Cuellar-Rodriguez</name>
<affiliation><nlm:aff id="aff5">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hsu, Amy P" sort="Hsu, Amy P" uniqKey="Hsu A" first="Amy P." last="Hsu">Amy P. Hsu</name>
<affiliation><nlm:aff id="aff5">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dyack, Sarah" sort="Dyack, Sarah" uniqKey="Dyack S" first="Sarah" last="Dyack">Sarah Dyack</name>
<affiliation><nlm:aff id="aff6">Department of Pediatrics, Maritime Medical Genetics Service, IWK Health Centre and Dalhousie University, Halifax, NS;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fernandez, Conrad V" sort="Fernandez, Conrad V" uniqKey="Fernandez C" first="Conrad V." last="Fernandez">Conrad V. Fernandez</name>
<affiliation><nlm:aff id="aff7">Departments of Pediatrics and Bioethics, IWK Health Centre and Dalhousie University, Halifax, NS;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chong, Chan Eng" sort="Chong, Chan Eng" uniqKey="Chong C" first="Chan-Eng" last="Chong">Chan-Eng Chong</name>
<affiliation><nlm:aff id="aff8">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">School of Medicine, University of Adelaide, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Babic, Milena" sort="Babic, Milena" uniqKey="Babic M" first="Milena" last="Babic">Milena Babic</name>
<affiliation><nlm:aff id="aff8">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bardy, Peter G" sort="Bardy, Peter G" uniqKey="Bardy P" first="Peter G." last="Bardy">Peter G. Bardy</name>
<affiliation><nlm:aff id="aff1">Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shimamura, Akiko" sort="Shimamura, Akiko" uniqKey="Shimamura A" first="Akiko" last="Shimamura">Akiko Shimamura</name>
<affiliation><nlm:aff id="aff10">Fred Hutchinson Cancer Research Center, Seattle, WA;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff11">Seattle Children's Hospital, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zhang, Michael Y" sort="Zhang, Michael Y" uniqKey="Zhang M" first="Michael Y." last="Zhang">Michael Y. Zhang</name>
<affiliation><nlm:aff id="aff10">Fred Hutchinson Cancer Research Center, Seattle, WA;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff12">Department of Genome Sciences and Department of Medicine, University of Washington, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Walsh, Tom" sort="Walsh, Tom" uniqKey="Walsh T" first="Tom" last="Walsh">Tom Walsh</name>
<affiliation><nlm:aff id="aff12">Department of Genome Sciences and Department of Medicine, University of Washington, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name>
<affiliation><nlm:aff id="aff5">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hickstein, Dennis D" sort="Hickstein, Dennis D" uniqKey="Hickstein D" first="Dennis D." last="Hickstein">Dennis D. Hickstein</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff13">Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Horwitz, Marshall S" sort="Horwitz, Marshall S" uniqKey="Horwitz M" first="Marshall S." last="Horwitz">Marshall S. Horwitz</name>
<affiliation><nlm:aff id="aff2">Department of Pathology, University of Washington School of Medicine, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hahn, Christopher N" sort="Hahn, Christopher N" uniqKey="Hahn C" first="Christopher N." last="Hahn">Christopher N. Hahn</name>
<affiliation><nlm:aff id="aff8">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">School of Medicine, University of Adelaide, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Scott, Hamish S" sort="Scott, Hamish S" uniqKey="Scott H" first="Hamish S." last="Scott">Hamish S. Scott</name>
<affiliation><nlm:aff id="aff8">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">School of Medicine, University of Adelaide, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff14">School of Molecular and Biomedical Science, University of Adelaide, SA, Adelaide, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Harvey, Natasha L" sort="Harvey, Natasha L" uniqKey="Harvey N" first="Natasha L." last="Harvey">Natasha L. Harvey</name>
<affiliation><nlm:aff id="aff1">Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">School of Medicine, University of Adelaide, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
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<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3277359</idno>
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<idno type="doi">10.1182/blood-2011-08-374363</idno>
<date when="2012">2012</date>
<idno type="wicri:Area/Pmc/Corpus">002C69</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Loss-of-function germline <italic>GATA2</italic>
mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature</title>
<author><name sortKey="Kazenwadel, Jan" sort="Kazenwadel, Jan" uniqKey="Kazenwadel J" first="Jan" last="Kazenwadel">Jan Kazenwadel</name>
<affiliation><nlm:aff id="aff1">Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Secker, Genevieve A" sort="Secker, Genevieve A" uniqKey="Secker G" first="Genevieve A." last="Secker">Genevieve A. Secker</name>
<affiliation><nlm:aff id="aff1">Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Liu, Yajuan J" sort="Liu, Yajuan J" uniqKey="Liu Y" first="Yajuan J." last="Liu">Yajuan J. Liu</name>
<affiliation><nlm:aff id="aff2">Department of Pathology, University of Washington School of Medicine, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rosenfeld, Jill A" sort="Rosenfeld, Jill A" uniqKey="Rosenfeld J" first="Jill A." last="Rosenfeld">Jill A. Rosenfeld</name>
<affiliation><nlm:aff id="aff3">Signature Genomics, PerkinElmer, Spokane, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wildin, Robert S" sort="Wildin, Robert S" uniqKey="Wildin R" first="Robert S." last="Wildin">Robert S. Wildin</name>
<affiliation><nlm:aff id="aff4">St Luke's Children's Hospital, Pediatric Genetics, and State of Idaho Genetics Program, Department of Health and Welfare, Boise, ID;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cuellar Rodriguez, Jennifer" sort="Cuellar Rodriguez, Jennifer" uniqKey="Cuellar Rodriguez J" first="Jennifer" last="Cuellar-Rodriguez">Jennifer Cuellar-Rodriguez</name>
<affiliation><nlm:aff id="aff5">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hsu, Amy P" sort="Hsu, Amy P" uniqKey="Hsu A" first="Amy P." last="Hsu">Amy P. Hsu</name>
<affiliation><nlm:aff id="aff5">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dyack, Sarah" sort="Dyack, Sarah" uniqKey="Dyack S" first="Sarah" last="Dyack">Sarah Dyack</name>
<affiliation><nlm:aff id="aff6">Department of Pediatrics, Maritime Medical Genetics Service, IWK Health Centre and Dalhousie University, Halifax, NS;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fernandez, Conrad V" sort="Fernandez, Conrad V" uniqKey="Fernandez C" first="Conrad V." last="Fernandez">Conrad V. Fernandez</name>
<affiliation><nlm:aff id="aff7">Departments of Pediatrics and Bioethics, IWK Health Centre and Dalhousie University, Halifax, NS;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chong, Chan Eng" sort="Chong, Chan Eng" uniqKey="Chong C" first="Chan-Eng" last="Chong">Chan-Eng Chong</name>
<affiliation><nlm:aff id="aff8">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">School of Medicine, University of Adelaide, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Babic, Milena" sort="Babic, Milena" uniqKey="Babic M" first="Milena" last="Babic">Milena Babic</name>
<affiliation><nlm:aff id="aff8">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bardy, Peter G" sort="Bardy, Peter G" uniqKey="Bardy P" first="Peter G." last="Bardy">Peter G. Bardy</name>
<affiliation><nlm:aff id="aff1">Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shimamura, Akiko" sort="Shimamura, Akiko" uniqKey="Shimamura A" first="Akiko" last="Shimamura">Akiko Shimamura</name>
<affiliation><nlm:aff id="aff10">Fred Hutchinson Cancer Research Center, Seattle, WA;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff11">Seattle Children's Hospital, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zhang, Michael Y" sort="Zhang, Michael Y" uniqKey="Zhang M" first="Michael Y." last="Zhang">Michael Y. Zhang</name>
<affiliation><nlm:aff id="aff10">Fred Hutchinson Cancer Research Center, Seattle, WA;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff12">Department of Genome Sciences and Department of Medicine, University of Washington, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Walsh, Tom" sort="Walsh, Tom" uniqKey="Walsh T" first="Tom" last="Walsh">Tom Walsh</name>
<affiliation><nlm:aff id="aff12">Department of Genome Sciences and Department of Medicine, University of Washington, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name>
<affiliation><nlm:aff id="aff5">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hickstein, Dennis D" sort="Hickstein, Dennis D" uniqKey="Hickstein D" first="Dennis D." last="Hickstein">Dennis D. Hickstein</name>
<affiliation><nlm:aff wicri:cut="; and" id="aff13">Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Horwitz, Marshall S" sort="Horwitz, Marshall S" uniqKey="Horwitz M" first="Marshall S." last="Horwitz">Marshall S. Horwitz</name>
<affiliation><nlm:aff id="aff2">Department of Pathology, University of Washington School of Medicine, Seattle, WA;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hahn, Christopher N" sort="Hahn, Christopher N" uniqKey="Hahn C" first="Christopher N." last="Hahn">Christopher N. Hahn</name>
<affiliation><nlm:aff id="aff8">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">School of Medicine, University of Adelaide, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Scott, Hamish S" sort="Scott, Hamish S" uniqKey="Scott H" first="Hamish S." last="Scott">Hamish S. Scott</name>
<affiliation><nlm:aff id="aff8">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">School of Medicine, University of Adelaide, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff14">School of Molecular and Biomedical Science, University of Adelaide, SA, Adelaide, Australia</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Harvey, Natasha L" sort="Harvey, Natasha L" uniqKey="Harvey N" first="Natasha L." last="Harvey">Natasha L. Harvey</name>
<affiliation><nlm:aff id="aff1">Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff9">School of Medicine, University of Adelaide, Adelaide, Australia;</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Blood</title>
<idno type="ISSN">0006-4971</idno>
<idno type="eISSN">1528-0020</idno>
<imprint><date when="2012">2012</date>
</imprint>
</series>
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<front><div type="abstract" xml:lang="en"><p>Recent work has established that heterozygous germline <italic>GATA2</italic>
mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), “MonoMAC” syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense <italic>GATA2</italic>
mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift <italic>GATA2</italic>
mutation (p.Leu332Thrfs*53), another with MDS harboring a <italic>GATA2</italic>
splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the <italic>GATA2</italic>
locus. Intriguingly, 2 MDS/AML or “MonoMAC” syndrome patients with <italic>GATA2</italic>
deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline <italic>GATA2</italic>
mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of <italic>GATA2</italic>
, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Blood</journal-id>
<journal-id journal-id-type="hwp">bloodjournal</journal-id>
<journal-id journal-id-type="pmc">blood</journal-id>
<journal-id journal-id-type="publisher-id">Blood</journal-id>
<journal-title-group><journal-title>Blood</journal-title>
</journal-title-group>
<issn pub-type="ppub">0006-4971</issn>
<issn pub-type="epub">1528-0020</issn>
<publisher><publisher-name>American Society of Hematology</publisher-name>
<publisher-loc>Washington, DC</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">22147895</article-id>
<article-id pub-id-type="pmc">3277359</article-id>
<article-id pub-id-type="publisher-id">2011/374363</article-id>
<article-id pub-id-type="doi">10.1182/blood-2011-08-374363</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Myeloid Neoplasia</subject>
</subj-group>
<subj-group subj-group-type="heading"><subject>Vascular Biology</subject>
</subj-group>
</article-categories>
<title-group><article-title>Loss-of-function germline <italic>GATA2</italic>
mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kazenwadel</surname>
<given-names>Jan</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="author-notes" rid="FN1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Secker</surname>
<given-names>Genevieve A.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="author-notes" rid="FN1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Yajuan J.</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
<xref ref-type="author-notes" rid="FN1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rosenfeld</surname>
<given-names>Jill A.</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wildin</surname>
<given-names>Robert S.</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cuellar-Rodriguez</surname>
<given-names>Jennifer</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hsu</surname>
<given-names>Amy P.</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dyack</surname>
<given-names>Sarah</given-names>
</name>
<xref ref-type="aff" rid="aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fernandez</surname>
<given-names>Conrad V.</given-names>
</name>
<xref ref-type="aff" rid="aff7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chong</surname>
<given-names>Chan-Eng</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
<xref ref-type="aff" rid="aff9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Babic</surname>
<given-names>Milena</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bardy</surname>
<given-names>Peter G.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shimamura</surname>
<given-names>Akiko</given-names>
</name>
<xref ref-type="aff" rid="aff10">10</xref>
<xref ref-type="aff" rid="aff11">11</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Michael Y.</given-names>
</name>
<xref ref-type="aff" rid="aff10">10</xref>
<xref ref-type="aff" rid="aff12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Walsh</surname>
<given-names>Tom</given-names>
</name>
<xref ref-type="aff" rid="aff12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Holland</surname>
<given-names>Steven M.</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hickstein</surname>
<given-names>Dennis D.</given-names>
</name>
<xref ref-type="aff" rid="aff13">13</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Horwitz</surname>
<given-names>Marshall S.</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hahn</surname>
<given-names>Christopher N.</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
<xref ref-type="aff" rid="aff9">9</xref>
<xref ref-type="author-notes" rid="FN1">*</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Scott</surname>
<given-names>Hamish S.</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
<xref ref-type="aff" rid="aff9">9</xref>
<xref ref-type="aff" rid="aff14">14</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Harvey</surname>
<given-names>Natasha L.</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff9">9</xref>
</contrib>
<aff id="aff1"><label>1</label>
Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</aff>
<aff id="aff2"><label>2</label>
Department of Pathology, University of Washington School of Medicine, Seattle, WA;</aff>
<aff id="aff3"><label>3</label>
Signature Genomics, PerkinElmer, Spokane, WA;</aff>
<aff id="aff4"><label>4</label>
St Luke's Children's Hospital, Pediatric Genetics, and State of Idaho Genetics Program, Department of Health and Welfare, Boise, ID;</aff>
<aff id="aff5"><label>5</label>
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD;</aff>
<aff id="aff6"><label>6</label>
Department of Pediatrics, Maritime Medical Genetics Service, IWK Health Centre and Dalhousie University, Halifax, NS;</aff>
<aff id="aff7"><label>7</label>
Departments of Pediatrics and Bioethics, IWK Health Centre and Dalhousie University, Halifax, NS;</aff>
<aff id="aff8"><label>8</label>
Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia;</aff>
<aff id="aff9"><label>9</label>
School of Medicine, University of Adelaide, Adelaide, Australia;</aff>
<aff id="aff10"><label>10</label>
Fred Hutchinson Cancer Research Center, Seattle, WA;</aff>
<aff id="aff11"><label>11</label>
Seattle Children's Hospital, Seattle, WA;</aff>
<aff id="aff12"><label>12</label>
Department of Genome Sciences and Department of Medicine, University of Washington, Seattle, WA;</aff>
<aff id="aff13"><label>13</label>
Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD; and</aff>
<aff id="aff14"><label>14</label>
School of Molecular and Biomedical Science, University of Adelaide, SA, Adelaide, Australia</aff>
</contrib-group>
<author-notes><fn fn-type="equal" id="FN1"><label>*</label>
<p>J.K., G.A.S., Y.J.L., and C.N.H. contributed equally to this study.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>2</day>
<month>2</month>
<year>2012</year>
</pub-date>
<pub-date pub-type="epreprint"><day>6</day>
<month>12</month>
<year>2011</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>2</day>
<month>2</month>
<year>2013</year>
</pub-date>
<pmc-comment> PMC Release delay is 12 months and 0 days and was based on the
. </pmc-comment>
<volume>119</volume>
<issue>5</issue>
<fpage>1283</fpage>
<lpage>1291</lpage>
<history><date date-type="received"><day>22</day>
<month>8</month>
<year>2011</year>
</date>
<date date-type="accepted"><day>23</day>
<month>11</month>
<year>2011</year>
</date>
</history>
<permissions><copyright-statement>© 2012 by The American Society of Hematology</copyright-statement>
<copyright-year>2012</copyright-year>
</permissions>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zh800512001283.pdf"></self-uri>
<abstract><p>Recent work has established that heterozygous germline <italic>GATA2</italic>
mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), “MonoMAC” syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense <italic>GATA2</italic>
mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift <italic>GATA2</italic>
mutation (p.Leu332Thrfs*53), another with MDS harboring a <italic>GATA2</italic>
splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the <italic>GATA2</italic>
locus. Intriguingly, 2 MDS/AML or “MonoMAC” syndrome patients with <italic>GATA2</italic>
deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurring us to investigate whether GATA2 plays a role in the lymphatic vasculature. We demonstrate here that GATA2 protein is present at high levels in lymphatic vessel valves and that GATA2 controls the expression of genes important for programming lymphatic valve development. Our data expand the phenotypes associated with germline <italic>GATA2</italic>
mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of <italic>GATA2</italic>
, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.</p>
</abstract>
<funding-group><award-group><funding-source id="CS100">National Institutes of Health</funding-source>
<award-id rid="CS100">R01DK058161</award-id>
<award-id rid="CS100">T32GM007266</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
</pmc>
</record>
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