|
Status Report: Genes which cause Macular Degeneration and Similar Retinal
Disorders by Philip Filner, Ph.D.
In the past few years a great deal of progress has been made in finding the mutant genes responsible for
inherited forms of macular degeneration. In some cases, the mutated protein and its function have also been identified. These discoveries can be expected to lead to greatly improved
understanding of how macular degeneration comes about. That knowledge should provide the basis for devising ways to intervene in these inherited forms of macular degeneration, and the
far more common age related macular degeneration, some of which also has a genetic component.
Best's Vitelliform Macular Dystrophy Best's disease is inherited as an autosomal dominant, but with
quite variable expression and time of onset of symptoms. Perhaps its most distinctive characteristic is the appearance at one stage of a large central deposit of drusen with the
appearance of an egg yolk. The gene has been cloned and sequenced. The protein it encodes has been named bestrophin, but its function is not yet known. Several distinct mutations
in the bestrophin gene have been found among families with Best's disease, each resulting in a specific amino acid substitution. Mutations in the bestrophin gene do not appear to
increase the probability of development of age related macular degeneration.
Doyne's Honeycomb Retinal Dystrophy Doyne's disease is form of macular degeneration which is inherited
as if caused by an autosomal dominant mutation. The disease usually becomes manifest in early childhood. The gene has been has been localized to a portion of the short arm of
chromosome 2, 2p16 - 21, near marker D2S378, which is also close to the gene which causes Malattia leventinese form of macular degeneration (see below). Recently, a gene and the
protein it encodes has been identified which is mutated in both Doyne's and Malattia leventinese forms of macular degeneration. The protein is called EGF-containing fibrillin-like
extracellular matrix protein, and the gene is called EFEMP. The same amino acid substitution mutation is present in individuals with Doyne's or Malattia leventinese macular
degeneration, which suggests that the two diseases have a common cause. Fundus flavimaculus This is essentially the same as Stargardt's disease (see
below), except that the age at which symptoms appear is usually in the 20's, while Stargardt's disease typically becomes manifest during childhood or teen year. A particular mutation
in the abcr gene has been found in people with Fundus Flavimaculus. Malattia leventinenese This is a dominantly inherited form of macular degeneration which develops in middle age or later. It results in a characteristic
pattern of radially arrayed drusen deposits. The mutant gene has been localized to a particular region of chromosome 2, between markers D2S2316 and D2S378, but has not yet been cloned
and sequenced. Recently, a mutant gene and the protein it encodes were identified in people with Malattia leventinese and Doyne's honeycomb retinal dystrophy (see Doyne's above). This
disease is not associated with mutations in abcr (see Stargardt's disease) or TIMP-3 (see Sorsby's fundus dystrophy). Sorsby's fundus dystrophy This form of macular degeneration
is inherited in a dominant fashion, and, like Malattia leventinese, produces symptoms relatively late in life.The gene responsible has been cloned and sequenced. Among the symptoms
are choroidal neovascularizations. The protein encoded by the gene has been identified as a tissue inhibitor of metalloproteinases-3, so is known as TIMP-3. Immunocytological methods
have been used to localize the sites of synthesis and accumulation of this protein. It is made in the Retinal Pigment Epithelium (RPE) and is incorporated into Bruch's membrane, which
separates the RPE from the choroid.. It has been suggested that faulty TIMP-3 in Bruch's membrane permits the protein called vascular endothelial growth factor (VEGF), which is made
by the RPE, to cross Bruch's membrane and stimulate neovascularization in the choroid. Supporting evidence for this idea comes from the finding that normal TIMP-3 has been shown to
inhibit the stimulation of neovascularization by VEGF. Drusen deposits between the RPE and Bruch's membrane also react with antibodies against TIMP-3. Stargardt's disease The most common form of Stargardt's disease is inherited as if caused by an autosomal recessive mutation. The gene has been cloned and
sequenced, and the protein it encodes has been identified. The gene is called the abcr gene. It is a member of the ATP Binding Cassette family of genes. The proteins encoded by that
family of genes share a domain for binding ATP. These proteins function in energy-dependent transport of specific biomolecules across membranes, in many different types of organisms.
Mutations in abc genes often result n major changes in disease resistance and antibiotic resistance, because the transport of a key bioactive molecule is affected. The abcr gene is
expressed in the rods and cones of the retina. The protein abcr encodes occurs at the rim of the photoreceptor outer segments, and is known as the Rim protein. The Rim protein
functions in the transport of retinal, the "spent" form of cis-retinol, the pigment portion of the photoreceptor pigment-protein complex, rhodopsin. It is believed that
retinal is transported to the RPE, where it is regenerated and then returned to the rods and cones for complexing with opsin so it can function in another cycle of photoreception.
|
|
