Candidate gene analysis in primary lymphedema.

[lymphedemapeople]

Candidate gene analysis in primary lymphedema.

Lymphat Res Biol. 2008

Ferrell RE, Kimak MA, Lawrence EC, Finegold DN.
University of Pittsburgh, Department of Human Genetics, Pittsburgh,
Pennsylvania.

Abstract Background: Primary lymphedema, the accumulation of protein-
rich fluid in the interstitial space, is the clinical manifestation of
mutations involved in lymphatic development and function. Mutations in
three genes, VEGFR3, FOXC2, and SOX18, cause primary lymphedema.
However, mutations in these three genes only account for a fraction of
primary lymphedema. To identify other genes mutated in primary
lymphedema, we resequenced twenty-five biologically plausible
candidate genes for lymphedema in a large collection of primary
lymphedema families. Methods and Results: Candidate genes were
selected on the basis of gene expression in lymphatic endothelial
cells, differential antigenic expression in lymphatics, and mouse
studies of lymphatic development. The gene sequence was downloaded
from GenBank and sequence primers designed to amplify 1 Kb of the 5'
sequence, exons and flanking intron-exon boundaries, and 500 bp of the
UTR of each gene. No common causative mutations were observed among
the 25 genes screened. Single mutations were observed in elastin
microfibril interfacer (EMILIN1), lymphocyte cytosolic protein 2
(LCP2), fatty acid binding protein 4 (FABP4), protein tyrosine kinase
SYK (SYK), neuropilin-2 (NRP2), SpSRY-box 17 (SOX17), vascular cell
adhesion molecule 1 (VCAM1), ROR orphan receptor C (RORC), and
vascular endothelial growth factor B (VEGFB). Among these, the
mutations in EMILIN1, RORC, LCP2, SYK, and VEGFB failed to segregate
with lymphedema. The mutations in FABP4 (2), NRP2, SOX17, and VACM1
are consistent with being causative mutations, but occur in families
too small to convincingly confirm cosegregation of mutation and
phenotype. Conclusion: We excluded mutation in 21 biological candidate
genes as a common cause of primary lymphedema. Mutations in FABP4,
NRP2, SOX17 and VCAM1 are consistent with causality and follow up of
these four genes are warranted. The evidence for FABP4 harboring
lymphedema mutations is discussed.

http://www.liebertonline.com/doi/abs/10.1089/lrb.2007.1022

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Pat O'Connor
Lymphedema People
http://www.lymphedemapeople.com