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 : 000848 ( PascalFrancis/Curation ); précédent : 000847; suivant : 000849Loss-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 [Australie] ; Genevieve A. Secker [Australie] ; Yajuan J. Liu [États-Unis] ; Jill A. Rosenfeld [États-Unis] ; Robert S. Wildin [États-Unis] ; Jennifer Cuellar-Rodriguez [États-Unis] ; Amy P. Hsu [États-Unis] ; Sarah Dyack [États-Unis] ; Conrad V. Fernandez [États-Unis] ; Chan-Eng Chong [Australie] ; Milena Babic [Australie] ; Peter G. Bardy [Australie] ; Akiko Shimamura [États-Unis] ; Michael Y. Zhang [États-Unis] ; Tom Walsh [États-Unis] ; Steven M. Holland [États-Unis] ; Dennis D. Hickstein [Australie] ; Marshall S. Horwitz [États-Unis] ; Christopher N. Hahn [Australie] ; Hamish S. Scott [Australie] ; Natasha L. Harvey [Australie]Source :
- Blood [ 0006-4971 ] ; 2012.
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- Pascal (Inist)
- Wicri :
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Abstract
Recent work has established that heterozygous germline GATA2 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 GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 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 GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">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</title><author><name sortKey="Kazenwadel, Jan" sort="Kazenwadel, Jan" uniqKey="Kazenwadel J" first="Jan" last="Kazenwadel">Jan Kazenwadel</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Haematology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>12 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="01"><s1>Division of Haematology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>12 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pathology, University of Washington School of Medicine</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="03"><s1>Signature Genomics, PerkinElmer</s1><s2>Spokane, WA</s2><s3>USA</s3><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="04"><s1>St Luke's Children's Hospital, Pediatric Genetics, and State of Idaho Genetics Program, Department of Health and Welfare</s1><s2>Boise, ID</s2><s3>USA</s3><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="05"><s1>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="05"><s1>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Dyack, Sarah" sort="Dyack, Sarah" uniqKey="Dyack S" first="Sarah" last="Dyack">Sarah Dyack</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Department of Pediatrics, Maritime Medical Genetics Service, IWK Health Centre and Dalhousie University</s1><s2>Halifax, NS</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="07"><s1>Departments of Pediatrics and Bioethics, IWK Health Centre and Dalhousie University</s1><s2>Halifax, NS</s2><s3>USA</s3><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="08"><s1>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Australie</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>School of Medicine, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></affiliation></author><author><name sortKey="Babic, Milena" sort="Babic, Milena" uniqKey="Babic M" first="Milena" last="Babic">Milena Babic</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="01"><s1>Division of Haematology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>12 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></affiliation></author><author><name sortKey="Shimamura, Akiko" sort="Shimamura, Akiko" uniqKey="Shimamura A" first="Akiko" last="Shimamura">Akiko Shimamura</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Fred Hutchinson Cancer Research Center</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>13 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Seattle Children's Hospital</s1><s2>Seattle</s2><s3>USA</s3><sZ>13 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="10"><s1>Fred Hutchinson Cancer Research Center</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>13 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genome Sciences and Department of Medicine, University of Washington</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>14 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Walsh, Tom" sort="Walsh, Tom" uniqKey="Walsh T" first="Tom" last="Walsh">Tom Walsh</name><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genome Sciences and Department of Medicine, University of Washington</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>14 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="05"><s1>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="13"><s1>Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD; and "School of Molecular and Biomedical Science, University of Adelaide</s1><s2>SA, Adelaide</s2><s3>AUS</s3><sZ>17 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pathology, University of Washington School of Medicine</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="08"><s1>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Australie</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>School of Medicine, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="08"><s1>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Australie</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>School of Medicine, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="01"><s1>Division of Haematology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>12 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>School of Medicine, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">12-0131180</idno><date when="2012">2012</date><idno type="stanalyst">PASCAL 12-0131180 INIST</idno><idno type="RBID">Pascal:12-0131180</idno><idno type="wicri:Area/PascalFrancis/Corpus">000109</idno><idno type="wicri:Area/PascalFrancis/Curation">000848</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">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</title><author><name sortKey="Kazenwadel, Jan" sort="Kazenwadel, Jan" uniqKey="Kazenwadel J" first="Jan" last="Kazenwadel">Jan Kazenwadel</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Division of Haematology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>12 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="01"><s1>Division of Haematology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>12 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pathology, University of Washington School of Medicine</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="03"><s1>Signature Genomics, PerkinElmer</s1><s2>Spokane, WA</s2><s3>USA</s3><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="04"><s1>St Luke's Children's Hospital, Pediatric Genetics, and State of Idaho Genetics Program, Department of Health and Welfare</s1><s2>Boise, ID</s2><s3>USA</s3><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="05"><s1>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="05"><s1>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Dyack, Sarah" sort="Dyack, Sarah" uniqKey="Dyack S" first="Sarah" last="Dyack">Sarah Dyack</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Department of Pediatrics, Maritime Medical Genetics Service, IWK Health Centre and Dalhousie University</s1><s2>Halifax, NS</s2><s3>USA</s3><sZ>8 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="07"><s1>Departments of Pediatrics and Bioethics, IWK Health Centre and Dalhousie University</s1><s2>Halifax, NS</s2><s3>USA</s3><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="08"><s1>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Australie</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>School of Medicine, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></affiliation></author><author><name sortKey="Babic, Milena" sort="Babic, Milena" uniqKey="Babic M" first="Milena" last="Babic">Milena Babic</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="01"><s1>Division of Haematology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>12 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></affiliation></author><author><name sortKey="Shimamura, Akiko" sort="Shimamura, Akiko" uniqKey="Shimamura A" first="Akiko" last="Shimamura">Akiko Shimamura</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Fred Hutchinson Cancer Research Center</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>13 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Seattle Children's Hospital</s1><s2>Seattle</s2><s3>USA</s3><sZ>13 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="10"><s1>Fred Hutchinson Cancer Research Center</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>13 aut.</sZ><sZ>14 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genome Sciences and Department of Medicine, University of Washington</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>14 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Walsh, Tom" sort="Walsh, Tom" uniqKey="Walsh T" first="Tom" last="Walsh">Tom Walsh</name><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Department of Genome Sciences and Department of Medicine, University of Washington</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>14 aut.</sZ><sZ>15 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="05"><s1>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>16 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="13"><s1>Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD; and "School of Molecular and Biomedical Science, University of Adelaide</s1><s2>SA, Adelaide</s2><s3>AUS</s3><sZ>17 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="02"><s1>Department of Pathology, University of Washington School of Medicine</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>18 aut.</sZ></inist:fA14><country>États-Unis</country></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 wicri:level="1"><inist:fA14 i1="08"><s1>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Australie</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>School of Medicine, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="08"><s1>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></inist:fA14><country>Australie</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>School of Medicine, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></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 wicri:level="1"><inist:fA14 i1="01"><s1>Division of Haematology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>12 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>School of Medicine, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>21 aut.</sZ></inist:fA14><country>Australie</country></affiliation></author></analytic><series><title level="j" type="main">Blood</title><title level="j" type="abbreviated">Blood</title><idno type="ISSN">0006-4971</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Blood</title><title level="j" type="abbreviated">Blood</title><idno type="ISSN">0006-4971</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acute myelogenous leukemia</term><term>Genetics</term><term>Germ line</term><term>Hematology</term><term>Human</term><term>Lymphatic</term><term>Lymphatic system</term><term>Lymphedema</term><term>Mutation</term><term>Myelodysplastic syndrome</term><term>Primary</term><term>Transcription factor GATA2</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Syndrome myélodysplasique</term><term>Lymphoedème</term><term>Lignée germinale</term><term>Facteur transcription GATA2</term><term>Mutation</term><term>Génétique</term><term>Homme</term><term>Leucémie aiguë myéloblastique</term><term>Primaire</term><term>Lymphatique</term><term>Système lymphatique</term><term>Hématologie</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Recent work has established that heterozygous germline GATA2 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 GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs<sup>*</sup>53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 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 GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0006-4971</s0></fA01><fA03 i2="1"><s0>Blood</s0></fA03><fA05><s2>119</s2></fA05><fA06><s2>5</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>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</s1></fA08><fA11 i1="01" i2="1"><s1>KAZENWADEL (Jan)</s1></fA11><fA11 i1="02" i2="1"><s1>SECKER (Genevieve A.)</s1></fA11><fA11 i1="03" i2="1"><s1>LIU (Yajuan J.)</s1></fA11><fA11 i1="04" i2="1"><s1>ROSENFELD (Jill A.)</s1></fA11><fA11 i1="05" i2="1"><s1>WILDIN (Robert S.)</s1></fA11><fA11 i1="06" i2="1"><s1>CUELLAR-RODRIGUEZ (Jennifer)</s1></fA11><fA11 i1="07" i2="1"><s1>HSU (Amy P.)</s1></fA11><fA11 i1="08" i2="1"><s1>DYACK (Sarah)</s1></fA11><fA11 i1="09" i2="1"><s1>FERNANDEZ (Conrad V.)</s1></fA11><fA11 i1="10" i2="1"><s1>CHONG (Chan-Eng)</s1></fA11><fA11 i1="11" i2="1"><s1>BABIC (Milena)</s1></fA11><fA11 i1="12" i2="1"><s1>BARDY (Peter G.)</s1></fA11><fA11 i1="13" i2="1"><s1>SHIMAMURA (Akiko)</s1></fA11><fA11 i1="14" i2="1"><s1>ZHANG (Michael Y.)</s1></fA11><fA11 i1="15" i2="1"><s1>WALSH (Tom)</s1></fA11><fA11 i1="16" i2="1"><s1>HOLLAND (Steven M.)</s1></fA11><fA11 i1="17" i2="1"><s1>HICKSTEIN (Dennis D.)</s1></fA11><fA11 i1="18" i2="1"><s1>HORWITZ (Marshall S.)</s1></fA11><fA11 i1="19" i2="1"><s1>HAHN (Christopher N.)</s1></fA11><fA11 i1="20" i2="1"><s1>SCOTT (Hamish S.)</s1></fA11><fA11 i1="21" i2="1"><s1>HARVEY (Natasha L.)</s1></fA11><fA14 i1="01"><s1>Division of Haematology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>12 aut.</sZ><sZ>21 aut.</sZ></fA14><fA14 i1="02"><s1>Department of Pathology, University of Washington School of Medicine</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>18 aut.</sZ></fA14><fA14 i1="03"><s1>Signature Genomics, PerkinElmer</s1><s2>Spokane, WA</s2><s3>USA</s3><sZ>4 aut.</sZ></fA14><fA14 i1="04"><s1>St Luke's Children's Hospital, Pediatric Genetics, and State of Idaho Genetics Program, Department of Health and Welfare</s1><s2>Boise, ID</s2><s3>USA</s3><sZ>5 aut.</sZ></fA14><fA14 i1="05"><s1>Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>16 aut.</sZ></fA14><fA14 i1="06"><s1>Department of Pediatrics, Maritime Medical Genetics Service, IWK Health Centre and Dalhousie University</s1><s2>Halifax, NS</s2><s3>USA</s3><sZ>8 aut.</sZ></fA14><fA14 i1="07"><s1>Departments of Pediatrics and Bioethics, IWK Health Centre and Dalhousie University</s1><s2>Halifax, NS</s2><s3>USA</s3><sZ>9 aut.</sZ></fA14><fA14 i1="08"><s1>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>11 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ></fA14><fA14 i1="09"><s1>School of Medicine, University of Adelaide</s1><s2>Adelaide</s2><s3>AUS</s3><sZ>10 aut.</sZ><sZ>19 aut.</sZ><sZ>20 aut.</sZ><sZ>21 aut.</sZ></fA14><fA14 i1="10"><s1>Fred Hutchinson Cancer Research Center</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>13 aut.</sZ><sZ>14 aut.</sZ></fA14><fA14 i1="11"><s1>Seattle Children's Hospital</s1><s2>Seattle</s2><s3>USA</s3><sZ>13 aut.</sZ></fA14><fA14 i1="12"><s1>Department of Genome Sciences and Department of Medicine, University of Washington</s1><s2>Seattle, WA</s2><s3>USA</s3><sZ>14 aut.</sZ><sZ>15 aut.</sZ></fA14><fA14 i1="13"><s1>Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, MD; and "School of Molecular and Biomedical Science, University of Adelaide</s1><s2>SA, Adelaide</s2><s3>AUS</s3><sZ>17 aut.</sZ></fA14><fA20><s1>1283-1291</s1></fA20><fA21><s1>2012</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>3178</s2><s5>354000506743250290</s5></fA43><fA44><s0>0000</s0><s1>© 2012 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>49 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>12-0131180</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Blood</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>Recent work has established that heterozygous germline GATA2 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 GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs<sup>*</sup>53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 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 GATA2 mutations to include predisposition to primary lymphedema and suggest that complete haploinsufficiency or loss of function of GATA2, rather than missense mutations, is the key predisposing factor for lymphedema onset. Moreover, we reveal a crucial role for GATA2 in lymphatic vascular development.</s0></fC01><fC02 i1="01" i2="X"><s0>002B19B</s0></fC02><fC02 i1="02" i2="X"><s0>002B12B04</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Syndrome myélodysplasique</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Myelodysplastic syndrome</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Mielodisplastico síndrome</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Lymphoedème</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Lymphedema</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Linfedema</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Lignée germinale</s0><s5>09</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Germ line</s0><s5>09</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Línea germinal</s0><s5>09</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Facteur transcription GATA2</s0><s5>10</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Transcription factor GATA2</s0><s5>10</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Factor transcripción GATA2</s0><s5>10</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Mutation</s0><s5>11</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Mutation</s0><s5>11</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Mutación</s0><s5>11</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Génétique</s0><s5>12</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Genetics</s0><s5>12</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Genética</s0><s5>12</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Homme</s0><s5>13</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Human</s0><s5>13</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Hombre</s0><s5>13</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Leucémie aiguë myéloblastique</s0><s5>14</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Acute myelogenous leukemia</s0><s5>14</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Leucemia aguda mieloblástica</s0><s5>14</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Primaire</s0><s5>15</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Primary</s0><s5>15</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Primario</s0><s5>15</s5></fC03><fC03 i1="10" i2="X" l="FRE"><s0>Lymphatique</s0><s5>16</s5></fC03><fC03 i1="10" i2="X" l="ENG"><s0>Lymphatic</s0><s5>16</s5></fC03><fC03 i1="10" i2="X" l="SPA"><s0>Linfático</s0><s5>16</s5></fC03><fC03 i1="11" i2="X" l="FRE"><s0>Système lymphatique</s0><s5>17</s5></fC03><fC03 i1="11" i2="X" l="ENG"><s0>Lymphatic system</s0><s5>17</s5></fC03><fC03 i1="11" i2="X" l="SPA"><s0>Sistema linfático</s0><s5>17</s5></fC03><fC03 i1="12" i2="X" l="FRE"><s0>Hématologie</s0><s5>18</s5></fC03><fC03 i1="12" i2="X" l="ENG"><s0>Hematology</s0><s5>18</s5></fC03><fC03 i1="12" i2="X" l="SPA"><s0>Hematología</s0><s5>18</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Hémopathie maligne</s0><s2>NM</s2><s5>37</s5></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Malignant hemopathy</s0><s2>NM</s2><s5>37</s5></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Hemopatía maligna</s0><s2>NM</s2><s5>37</s5></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Cancer</s0><s2>NM</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Cancer</s0><s2>NM</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Cáncer</s0><s2>NM</s2></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Pathologie de l'appareil circulatoire</s0><s5>38</s5></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Cardiovascular disease</s0><s5>38</s5></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Aparato circulatorio patología</s0><s5>38</s5></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Pathologie des vaisseaux lymphatiques</s0><s5>39</s5></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Lymphatic vessel disease</s0><s5>39</s5></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Linfático patología</s0><s5>39</s5></fC07><fN21><s1>100</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist></record>Pour manipuler ce document sous Unix (Dilib)
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