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Published Online: 20 January 2015

HGF and MET Mutations in Primary and Secondary Lymphedema

Publication: Lymphatic Research and Biology
Volume 6, Issue Number 2

Abstract

Background: Lymphedema is the abnormal accumulation of protein-rich fluid in the interstitial space. Primary lymphedema is a rare genetic condition with both autosomal dominant and autosomal recessive modes of inheritance. Three genes, FLT4 (VEGFR3), FOXC2, and SOX18 cause varying forms of primary lymphedema. In industrialized countries, secondary lymphedema is usually associated with cancer therapy and/or trauma. Recent observations suggested that hepatocyte growth factor/high affinity hepatocyte growth factor receptor (HGF/MET) were new candidate lymphedema genes.
Methods and Results: The coding exons and flanking regions of HGF and MET were directly sequenced in 145 lymphedema probands, 59 unrelated women with secondary lymphedema following treatment for breast cancer, 21 individual patients with lymphedema and intestinal lymphangiectasia, and at least 159 unrelated ethnic matched control individuals. Mutations leading to truncation or missense changes in evolutionarily conserved residues of HGF and MET were identified. These mutations were not polymorphic in control individuals.
Conclusions: The identification of HGF/MET mutations in primary lymphedema, lymphedema/lymphangiectasia, and breast cancer-associated secondary lymphedema suggests that the HGF/MET pathway is causal or alters susceptibility for a broad range of lymphedema phenotypes. The HGF/MET pathway provides a new target for the prevention and/or treatment of lymphedema.

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Published In

cover image Lymphatic Research and Biology
Lymphatic Research and Biology
Volume 6Issue Number 2June 2008
Pages: 65 - 68
PubMed: 18564920

History

Published online: 20 January 2015
Published in print: June 2008

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Authors

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David N. Finegold
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania.
DNF, CJB, and REF contributed equally to this work.
Vivien Schacht
Department of Dermatology, University Medical Center, Freiburg, Germany.
Mark A. Kimak
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Elizabeth C. Lawrence
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Etelka Foeldi
Foeldi Clinic for Lymphology, Hinterzarten, Germany
Jenny M. Karlsson
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Catherine J. Baty
Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
DNF, CJB, and REF contributed equally to this work.
Robert E. Ferrell
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
DNF, CJB, and REF contributed equally to this work.

Notes

Supported in part by a grant from the American Cancer Society, NIH Grant HD 37243, and Deutsche Forschungsgemeinschaft, SFBTR23.
Address reprint requests to:David Finegold, M.D.A300 Crabtree HallDepartment of Human GeneticsGraduate School of Public Health130 Desoto StreetPittsburgh, PA 15261E-mail: [email protected]

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