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6 Patofisiologi
Photoreceptor cells are susceptible to cellular stress - their degeneration and loss is a major cause of blindness.
Many genes have identified for the inherited and highly heterogeneous disorders resulting from photoreceptor
degeneration. One of the most common form is retinitis pigmentosa (RP) and its patterns of inheritance are
varied - some are autosomal dominant (adRP), others are autosomal recessive (arRP), a smaller fraction are X-
linked (XLRP) and between 30 to 50% have not yet been class

ified. Other disorders include Bardet-Biedl syndrome (BBS), macular and age-related macular degeneration (MD,
AMD), Leber congenital amaurosis (LCA), cone and cone-rod degeneration (CD, CRD). RP may occur alone or
non-syndromic or in combination with other disorders, such as the Usher syndrome. Mutations in the same gene
can cause different phenotypes, such as the many mutations in rhodopsin receptor (Rho) that cause adRP or
arRP. Many RP mutations are in genes involved in the phototransduction and the metabolic visual cycle
pathways. To access the diagram for the normal retinoid cycle pathway, click here . The response to light in the
vertebrate retina is mediated by two photoreceptor types: the rods that mediate vision in dim light and the cones
that mediate bright light and color vision. Both are G-protein coupled receptors (GPCR) that activate the specific
heterotrimeric G protein transducin complex upon their own activation by the visual pigment - the vitamin A-
derived 11-cis retinal. The one rod gene (Rho) and three cone genes are collectively known as opsins. In the
absence of light, 11-cis retinal acts as an inverse agonist that constrains the receptor in an inactive conformation.
Upon light stimulation, the chromophore is isomerized to all-trans retinal; a series of conformational changes in
the photoreceptor follow and the isomerized chromophore is released. Several enzymes catalyze the reduction,
esterification, isomerization and final oxidation of substrates back to the 11-cis retinal in the metabolic visual
cycle to assure the continued visual phototransduction response to light. Briefly, all-trans retinal is first reduced to
all-trans retinol by specific retinol dehydrogenases (RDHs); its transport to the cytoplasmic side of the membrane
to serve as the substrate of the enzymes is mediated by the ATP-binding cassette transporter Abca4. All-trans
retinol is esterified to retinyl esters by Lrat. Isomerization of all-trans retinol/retinyl esters to 11-cis retinol is
carried out by Rpe65. Retinols are bound by Rbp3 in the extracellular space and by Rbp1 in the retinal pigment
epithelium (RPE). The oxidation of 11-cis retinol to 11-cis retinal is carried by 11-cis retinol dehydrogenases; the
newly synthesized chromophore is bound by Rlbp1 which mediates its transport to the receptor site on the
membrane. Mutations in many of the genes in the visual cycle have been associated with both the arRP and
adRP and with other forms of photoreceptors degeneration. The genes whose mutations display a dominant
phenotype are highlighted. In addition to the mutant genes in this and the visual phototransduction pathway,
other RP and photoreceptor degeneration disorders associated genes affect process/pathway categories such as
ciliary transport and channel activity, retinal development, metabolism and splicing (see other genes in RP in the
disease pathway). Impairment of the visual cycle can deplete the system of 11-cis retinal production and
therefore of the continued phototransduction response to light. Combined with rod defective visual transduction it
can result in decreased input to the visual cortex and diminished visual perception. Its augmentation with time
may underlie the progressive degeneration of the photoreceptor and associated blindness. To see the ontology
report for annotations, Gviewer and download, click here...
Photoreceptor cells are susceptible to cellular stress - their degeneration and loss is a major cause of blindness.
Many genes have identified for the inherited and highly heterogeneous disorders resulting and its patterns of
inheritance are varied - some are autosomal dominant (adRP), others are autosomal recessive (arRP), a smaller
fraction are X-linked (XLRP) and between 30 to 50% have not yet been classified. Other disorders include
Bardet-Biedl syndrome (BBS), macular and age-related macula

r degeneration (MD, AMD), Leber congenital amaurosis (LCA), cone and cone-rod degeneration (CD, CRD). RP
may occur alone or non-syndromic or in combination with other disorders, such as the Usher syndrome.
Mutations in the same gene can cause different phenotypes, such as the many mutations in rhodopsin receptor
(Rho) that cause adRP or arRP. Many RP mutations are in genes involved in the phototransduction and the
metabolic visual cycle pathways. The response to light in the vertebrate retina is mediated by two photoreceptor
types: the rods that mediate vision in dim light and the cones that mediate bright light and color vision. Both are
G-protein coupled receptors (GPCR) that activate the specific heterotrimeric G protein transducin complex upon
their own activation by the visual pigment - the vitamin A-derived 11-cis retinal. The one rod gene (Rho) and
three cone genes are collectively known as opsins. Some 200 point mutations have been described for Rho and
are associated with both adRP and arRP; they have been categorized into six classes with class I and II being
the more common. Upon activation, transducin activates the cGMP phoshodiesterase (Pde) complex; the
subsequent decrease in cGMP closes the cGMP-gated cation channels resulting in decreased calcium (Ca2+)
influx. Mutations in rod-specific Pde and in cGMP-gated channels are associated with arRP. Decrease in
intracellular Ca2+ also promotes the activation of guanylate cyclases and restoration of cGMP levels. The
enzymes are constitutively bound to activator proteins (GCAPs), Ca2+ binding proteins that inhibit the cyclases in
the presence of Ca2+ but stimulate them in its absence. Mutations in an activator gene have been associated
with adRP. GPCR signaling is controlled by several classes of proteins - the kinases that phosphorylate the
activated receptors which are then recognized by arrestins whose binding precludes re-binding of G-proteins; at
the G-protein level, by GTPase-activating proteins (GAPs) that increase the rate of G-protein GTP hydrolysis
leading to inactivation of the Galpha subunit. Sag is a specific arrestin whose mutations have been associated
with arRP. In the absence of light, 11-cis retinal acts as an inverse agonist that constrains the receptor in an
inactive conformation. Upon light stimulation, the chromophore is isomerized to all-trans retinal. Several enzymes
catalyze the transformation of substrates back to the 11-cis retinal in the metabolic visual cycle. Briefly, all-trans
retinal is first reduced to all-trans retinol by specific retinol dehydrogenases (RDHs); its transport to the
cytoplasmic side of the membrane to serve as the substrate of the enzymes is mediated by the Abca4
transporter. All-trans retinol is esterified to retinyl esters by Lrat. Isomerization to 11-cis retinol is carried out by
Rbp65. Retinols are bound by Rbp3 in the extracellular space and by Rbp1 in the retinal pigment epithelium
(RPE). Oxidation of 11-cis retinol to 11-cis retinal is carried out by 11-cis retinol dehydrogenases; the newly
synthesized chromophore is bound by Rlbp1 which mediates its transport to the receptor site on the membrane.
Many of these genes carry mutations and are associated with RP and other forms of photoreceptor degeneration.
Approximately one sixth of all RP patients have Usher (USH) syndrome characterized by both vision and hearing
loss. Clinically, the three types of Usher - USH1, 2 and 3 have been associated with five, three and one gene,
respectively; USH1 is the most severe form. The five genes in USH1 - collectively referred to as the USH1
interactome - are implicated in arRP along with one USH2 and the one USH3 gene. Their associations with
auditory mechanotransduction are better known - see the auditory mechanotransduction pathway; the precise
roles in visual phototransduction and altered pathways are still elusive but impaired ciliary transport/trafficking is
possible. Other RP and photoreceptor degeneration disorders associated genes affect process/pathway
categories such as ciliary transport and channel activity, retinal development, metabolism and splicing (several
are listed). The expression and targets of several microRNAs are important for the eye. Aberrant expression of
several miRNAs has been observed in mouse models of RP where the relatively few studies of miRNAs roles in
photoreceptor degeneration have been carried out

Rod and cone photoreceptor cell death in retinitis

pigmentosa. Rod cell death due to the deleterious genetic
mutations is associated with apoptosis, which involves the
activation of caspase-independent pathways including
poly-ADP-ribose-polymerase (PARP), calpain and histone
deacetylase (HDAC).