HGF and MET mutations in primary and secondary lymphedema.
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.


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.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 Desoto Street, Pittsburgh, PA 15261, USA. david.finegold@hgen.pitt.edu
David N
DN
Finegold
Vivien
V
Schacht
Mark A
MA
Kimak
Elizabeth C
EC
Lawrence
Etelka
E
Foeldi
Jenny M
JM
Karlsson
Catherine J
CJ
Baty
Robert E
RE
Ferrell
D005091:Exons; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008200:Lymphangiectasis / Q000209:etiology / Q000235:genetics*; D008209:Lymphedema / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000235:genetics*
D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met