Researchers discover gene mutation linked to lymphedema/ lymphatic dysfunction

[lymphedemapeople]

Researchers discover gene mutation linked to lymphatic dysfunction

May 27, 2010

Preface from PDF article ****Lymphedema is the clinical manifestation
of defects
in lymphatic structure or function. Mutations identified in genes
regulating
lymphatic development result in inherited lymphedema. No mutations
have yet been
identified in genes mediating lymphatic function that result in
inherited
lymphedema. Survey microarray studies comparing lymphatic and blood
endothelial
cells identified expression of several connexins in lymphatic
endothelial cells.
Additionally, gap junctions are implicated in maintaining lymphatic
flow.

By sequencing GJA1, GJA4, and GJC2 in a group of families with
dominantly
inherited lymphedema, we identified six probands with
unique missense mutations in GJC2 (encoding connexin [Cx] 47). Two
larger
families cosegregate lymphedema and GJC2 mutation
(LOD score ¼ 6.5). We hypothesize that missense mutations in GJC2
alter gap
junction function and disrupt lymphatic flow. Until
now, GJC2 mutations were only thought to cause dysmyelination, with
primary
expression of Cx47 limited to the central nervous
system. The identification of GJC2 mutations as a cause of primary
lymphedema
raises the possibility of novel gap-junction-modifying
agents as potential therapy for some forms of lymphedema.*****

A genetic mutation for inherited lymphedema associated with lymphatic
function
has been discovered that could help create new treatments for the
condition, say
researchers at the University of Pittsburgh Graduate School of Public
Health.
Their findings are reported in the June issue of the American Journal
of Human
Genetics.

Lymphedema, the swelling of body tissues caused by an accumulation of
fluid in a
blocked or damaged lymphatic system, affects more than 120 million
people
worldwide. The most common treatments are a combination of massage,
compression
garments or bandaging.

"Lymphedema was first described hundreds of years ago, and yet it
remains a very
poorly understood disease," said David N. Finegold, M.D., co-principal
investigator of the study and professor of human genetics, University
of
Pittsburgh Graduate School of Public Health. "Unfortunately, there is
no drug
available to cure or even treat it. Most people with inherited
lymphedema suffer
their entire lives with treatments that address symptom relief only."

The study is based on the University of Pittsburgh Lymphedema Family
Study,
which began collecting data from affected families in 1995 to learn
more about
the risk factors and causes of inherited, or primary, lymphedema.

Previous research has helped identify six genes linked to the
development of
lymphedema, but until now researchers had no insight into the genetic
factors
responsible for lymphatic vascular abnormalities.

In their study, Dr. Finegold and colleagues sequenced three genes
expressed in
families with primary lymphedema. Mutations in one of these genes,
GJC2, was
found in primary lymphedema families and are likely to impair the
ability of
cells to push fluid throughout the lymphatic system by interrupting
their
signaling.

Without proper signaling, cell contraction necessary for the movement
of fluid
did not occur, leading to its accumulation in soft body tissues.

"These results are significant because they give us insight into the
cell
mechanics that may underlie this condition," said Dr. Finegold. "With
further
research, we may be able to target this gene with drugs and improve
its
function."

More information PDF article:

http://www.upmc.com/mediarelations/newsreleases/2010/documents/ajhg0647_lofnq2.p\
df