People suffering from a severe retinal disease will sooner or later lose
their eyesight considerably, or even become completely blind. Those
affected, family members, researchers and doctors hope that this fate
might be avoided one day by a better understanding of the reasons for
this disease. Coordinated by the geneticist Ronald Roepman from
Nijemegen, an important step has now been made in this direction by an
international research team with the participation of the GSF – National
Research Center for Environment and Health: they identified a further
gene for the inherited retinal disease Leber Congenital Amaurosis (LCA)
and discovered first evidences of how it functions. This represents new
opportunities for gene therapy, which especially for LCA, is considered
as very promising since the disease is caused by a single mutation.
LCA causes blindness very early on – often shortly after or within a few
months of birth. The disease can be caused through a single mutation in
different genes; with the newly discovered LCA5 gene, ten
disease-causing genes had been identified so far which are responsible
for approx. 60 % of all LCA diseases. “All these deficiencies lead in
the end to the same symptoms, however, in order to treat the disease
efficiently with the individual patient, it is important to know which
gene mutation occurred in the specific case and what it causes”,
underlines Dr. Marius Ueffing (GSF Institute for Human Genetics), who
leads the project at GSF.
The LCA5 gene encodes the lebercilin, a so far unknown protein. Through
proteomic methods, Ueffing’s team could demonstrate that lebercilin
specifically interacts with other proteins which play a role in the
protein transport in the cells. Thus the scientists concluded that
lebercilin is relevant for the protein transport within the optical
cell: as shown by electro-microscopic pictures, within the optical cell
described as the photoreceptor, lebercilin binds the most to the
so-called cilium, the connection point between the interior and exterior
segments of the photoreceptor. Through this “molecular transport belt”,
the optical crimson must be also transported into the exterior segment
of the optical cell. The light reception takes place exactly here. If
the lebercilin synthesis is disturbed, the already used optical crimson
in the exterior segment cannot be replaced anymore and the eyesight is
lost, according to the researchers’ hypothesis.
Very similar transport processes also play a role in other body parts,
e.g. in the kidneys. Lebercilin is part of a complex network of proteins
which controls ciliary transport processes, or directly take part in
them. Disruptions in the cooperation of such molecular networks at the
protein interaction level often build the molecular basis of diseases.
In the case of ciliary diseases (ciliopathies), the restricted
functionalities of cilium cause deafness, blindness or even severe
syndrome diseases. LCA is therefore a good model which also enables to
gain more knowledge over other difficultly treatable diseases in the
long term.
LCA itself is so far incurable. However, patients and doctors set their
hopes high on gene therapy: since each type of LCA is caused by the
mutation of a single gene, the affected persons could be helped by
exchanging this gene. Such a LCA gene therapy has been already
successfully implemented for dogs who naturally suffer from LCA: the
treated dogs regained their permanent eyesight due to this therapy. A
clinical study of twelve human patients is currently being carried out
at a large-scale London hospital with encouraging results. If these
findings prove to be withstandable, there will also be gene therapy
available for LCA5 gene deficiencies in five to ten years time, says
Ueffing. “The affected persons urge for a faster procedure” underlines
Ueffing, “but researchers and doctors assume a big responsibility
concerning the development and implementation of gene therapies.
Therefore, very high safety standards must be set in this field.”
Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis
Anneke I den Hollander, Robert K Koenekoop, Moin D Mohamed, Heleen H
Arts, Karsten Boldt, Katherine V Towns, Tina Sedmak, Monika Beer,
Kerstin Nagel-Wolfrum, Martin McKibbin, Sharola Dharmaraj, Irma Lopez,
Lenka Ivings, Grange A Williams, Kelly Springell, C Geoff Woods, Hussain
Jafri, Yasmin Rashid, Tim M Strom, Bert van der Zwaag, Ilse Gosens,
Ferry F J Kersten, Erwin van Wijk, Joris A Veltman, Marijke N Zonneveld,
Sylvia E C van Beersum, Irene H Maumenee, Uwe Wolfrum, Michael E
Cheetham, Marius Ueffing, Frans P M Cremers, Chris F Inglehearn & Ronald
Roepman;
Nature Genetics Jul; 39(7) 2007:889-95; Nature Genetics advance online publication Published online: 3 June 2007; doi:10.1038/ng2066
GSF – National Research Center for Environment and Health
gsf.de