Ocular albinism type 1 (OA1) is the most common type of
ocular albinism
Ocular albinism is a form of albinism which, in contrast to oculocutaneous albinism, presents primarily in the eyes. There are multiple forms of ocular albinism, which are clinically similar.James, William; Berger, Timothy; Elston, Dirk (2005). ' ...
, with a prevalence rate of 1:50,000.
It is an inheritable classical
Mendelian
Mendelian inheritance (also known as Mendelism) is a type of biology, biological Heredity, inheritance following the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, an ...
type
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...
disorder wherein the
retinal pigment epithelium
The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells, and is firmly attached to the underlying choroid and overlying retinal visual ce ...
lacks pigment while hair and skin appear normal. Since it is usually an X-linked disorder, it occurs mostly in males, while females are carriers unless they are
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
.
About 60
missense
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense mu ...
and
nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
s,
insertions, and
deletions have been identified in ''Oa1''. Mutations in OA1 have been linked to defective
glycosylation
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not al ...
and thus improper intracellular transportation.
[Schiaffino, M.V., d'Addio, M., Alloni, A., Baschirotto, C., Valetti, C., Cortese, K., Puri, C., Bassi, M.T., Colla, C., De Luca, M., Tacchetti, C. and Ballabio, A. (1999). Ocular albinism: Evidence for a defect in an intracellular signal transduction system. ''Nature Genetics'' 23:108.]
The
eponym
An eponym is a person, a place, or a thing after whom or which someone or something is, or is believed to be, named. The adjectives which are derived from the word eponym include ''eponymous'' and ''eponymic''.
Usage of the word
The term ''epon ...
s of the name "Nettleship–Falls syndrome" are the ophthalmologists
Edward Nettleship
Edward Nettleship Fellow of the Royal Society, FRS Fellow of the Chemical Society, FCS (3 March 1845 – 30 October 1913) was an English ophthalmologist.
He was a native of Kettering. After finishing his medical studies at King's College London, ...
and
Harold Francis Falls.
Signs and symptoms
OA1 is recognized by many different symptoms. Reduced visual acuity is accompanied by involuntary movements of the eye termed as
nystagmus
Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...
.
Astigmatism
Astigmatism is a type of refractive error due to rotational asymmetry in the eye's refractive power. This results in distorted or blurred vision at any distance. Other symptoms can include eyestrain, headaches, and trouble driving at nig ...
is a condition wherein there occurs significant
refractive error
Refractive error, also known as refraction error, is a problem with focus (optics), focusing light accurately on the retina due to the shape of the human eye, eye and or cornea. The most common types of refractive error are myopia, near-sightedne ...
. Moreover, ocular albino eyes become crossed, a condition called 'lazy eyes' or
strabismus
Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...
. Since very little pigment is present the
iris
Iris most often refers to:
*Iris (anatomy), part of the eye
*Iris (mythology), a Greek goddess
* ''Iris'' (plant), a genus of flowering plants
* Iris (color), an ambiguous color term
Iris or IRIS may also refer to:
Arts and media
Fictional ent ...
becomes translucent and reflects light back. It appears green to violet. However, the most important part of the eye, the
fovea
Fovea () (Latin for "pit"; plural foveae ) is a term in anatomy. It refers to a pit or depression in a structure.
Human anatomy
*Fovea centralis of the retina
* Fovea buccalis or Dimple
* Fovea of the femoral head
* Trochlear fovea of the fr ...
which is responsible for acute vision, does not develop properly, probably indicating the role of
melanin
Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...
in the development stages of the eye. Some affected individuals may also develop
photophobia
Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of ...
/photodysphoria. All these symptoms are due to lack of pigmentation of the retina. Moreover, in an ocular albino eye, nerves from back of the eye to the brain may not follow the usual pattern of routing. In an ocular albino eye, more nerves cross from back of the eye to the opposite side of the brain instead of going to both sides of the brain as in a normal eye.
An ocular albino eye appears blueish pink in color with no pigmentation at all unlike a normal eye. Carrier women have regions of hypo- and hyper-pigmentation due to X-inactivation and partial iris transillumination and do not show any other symptoms exhibited by those affected by OA1.
Molecular biology
Human ''Oa1'' gene has been identified by positional cloning as a 40kb gene mapped to Xp22.3-Xp22.2.
Later, a mouse homolog of the human ''Oa1'' gene was also identified and cloned. It codes for a 404 amino acid long protein with up to three potential glycosylation sites. The transcript has been found to be expressing very well in retinal pigment epithelium and skin and to a much lesser extent in brain and adrenal glands.
Mutations in ''Oa1'' have been well characterized and studied using various techniques like
southern blot
A Southern blot is a method used in molecular biology for detection of a specific DNA sequence in DNA samples. Southern blotting combines transfer of electrophoresis-separated DNA fragments to a filter membrane and subsequent fragment detecti ...
analyses,
single-strand conformation polymorphism Single-strand conformation polymorphism (SSCP), or single-strand ''chain'' polymorphism, is defined as a conformational difference of single-stranded nucleotide sequences of identical length as induced by differences in the sequences under certain ...
and sequence analysis.
Most of these mutations have been reported to be occurring in the
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
and few in the trans-membrane regions but very rarely in the much conserved cytoplasmic C-terminus. Populations belonging to different ethnic groups have been extensively analyzed and a database has been created recording the details of mutations related to OA1. A total of 25 missense, 2 nonsense, 9 frameshift, and 5 splicing mutations have been reported till date.
In addition to these mutations, there also occur several deletions in one or many of the exons of ''Oa1'' gene, especially exon 2. These deletions are presumed to be because of unequal crossing-over due to the presence of flanking ''Alu'' regions. In some cases, the entire ''Oa1'' gene is deleted along with other contiguous genes. Many different polymorphisms have also been detected, mainly in intron 1.
Tissue-specific control of ''Oa1'' transcription is by a 617bp long E-box region bound by Mitf. Mitf has been shown to regulate expression of many melanosomal genes like TYR and TRP-1 through the E-box motif (CATGTG). Vetrini ''et al.'' have used adenoviral vectors to study tissue-specificity of ''Oa1'' transcription through Mitf and observed that this regulation in conserved in human ''Oa1'' gene.
Albinism
The term ''
albinism
Albinism is the congenital absence of melanin in an animal or plant resulting in white hair, feathers, scales and skin and pink or blue eyes. Individuals with the condition are referred to as albino.
Varied use and interpretation of the term ...
''
. ''albus'' means ‘white’refers to a heterogeneous group of congenital disorders in
melanin
Melanin (; from el, μέλας, melas, black, dark) is a broad term for a group of natural pigments found in most organisms. Eumelanin is produced through a multistage chemical process known as melanogenesis, where the oxidation of the amino ...
pigment biogenesis. Pigmentation process maybe affected in one or many ways due to mutations. Abnormal pigmentation maybe at the level of
embryogenesis
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...
in regions where
melanocyte
Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea),
the inner ear,
vaginal epithelium, meninges,
bones,
and heart.
...
s fail to populate. The melanin biosynthetic pathway may also be affected due to mutations. Sometimes one or many of the genes responsible for biogenesis of
organelle
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
s may be mutated.
Albinism may manifest itself as
oculocutaneous (OCA) or just ocular (OA). There occur at least ten different types of OCA and four types of OA.
[Hegde, M., Lewis, R.A. and Richards, C.S. (2002). Diagnostic DNA testing for X-linked ocular albinism (OA1) with a hierarchical mutation screening protocol. ''Genetic Testing'' 6(1):7.] OCA refers to a group of
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...
recessive disorders in which melanin is reduced or even absent leading to pale skin with increased risk of skin cancer. OCA1 is caused due to mutations in
tyrosinase
Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis otherwise known as the Raper Mason pathway. Firstly, the hydroxylat ...
gene affecting its catalytic or synthetic activity.
OCA2 is a condition where ''TYR'' gene is not mutated but the P
polypeptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
A p ...
is. Mutational defects in TRP-1 protein leads to OCA3.
Ocular albinism results from defects in the melanin system, which may arise from either defects in the OA1 receptor, or mutations of either the Tyr gene or P transporter.
Structure of OA1 protein
Human ''Oa1'' gene product was initially identified as a 60kDa protein formed from a 46-48kDa precursor.
The OA1 disease is due to defect in the OA1 receptor. This receptor has been shown to be similar to class C
G- protein coupled receptors (GPCR). OA1 receptor has a characteristic GPCR structure-7 transmembrane helices with 3 cytoplasmic loops and 3 extracellular loops and an extracellular N- terminus and cytoplasmic C-terminus. Recently the ligand activating this receptor was found.
A recent computational work has provided some insight into the three-dimensional structure of this protein and its dynamic interactions with its known ligands.
Localization of the OA1 protein
Shen, ''et al.'' created fusion proteins between OA1 and GFP.
Melanosomal localization of OA1 has been confirmed by immuno-electron microscopy and other techniques alike. Localization patterns of wild type OA1-GFP and mutated OA1-GFP were compared. The wild type OA1 localized to late endosomal or lysosomal compartments. This is supported by data from Samaraweera, ''et al.'' that OA1 colocalizes with Lamp1, which is a marker for late endosomal compartment. Hence, OA1 might traffick itself out of this compartment to the melanosomes.
In addition to retina and melanoma, OA1 protein product was also detected in human pigment cells like melanosomal membrane glycoprotein.
This suggests that OA1 might be involved in melanosome biogenesis. Coimmunoprecipitation studies of OA1 with G
β and G
αi in melanocyte extracts revealed its specific interaction with G
αi.
Further study have also shown that OA1 interact specifically with G
αi3 subtype. Moreover, since OA1 is an organellar GPCR, it may represent an unidentified pathway in the melanosome. Until recently, it was believed that the probable ligand for OA1 might be within the melanosomal lumen, maybe one of the components of the melanogenic pathway since it is so closely related to melanosome biogenesis.
This has been proved now.
Studies by Samaraweera, ''et al.'' revealed OA1 as an endolysosomal protein.
[Samaraweera, P., Shen, B., Newton, J.M., Barsh, G.S. and Orlow, S.J. (2001). The mouse ocular albinism 1 gene product is an endolysosomal protein. ''Experimental Eye Research'' 72:319.] Schiaffino, ''et al.'' already proved that it is an integral membrane protein.
Newton ''et al.'' have shown that it has three probable glycosylation sites. Furthermore, OA1 was found to be stimulated by α-melanocortin stimulating hormone but inhibited by agouti signal protein.
The fact that OA1 responds to melanin modifiers indicates its probable role in melanogenesis. Just like other melanosomal proteins TYR and TRP-1, processing of OA1 also occurs in the golgi.
[d'Addio, M., Pizzigoni, A., Bassi, M.T., Baschirotto, C., Valetti, C., Incerti, B., Clementi, M., De Luca, M., Ballabio, A. and Schiaffino, M.V. (2000). Defective intracellular transport and processing of OA1 is a major cause of ocular albinism type 1. ''Human Molecular Genetics'' 9(20):3011.] Endogenous OA1 protein expressed by normal human melanocytes is detected as a 60kDa protein.
Receptor-Ligand interactions
Very recently the orphan OA1 receptor has been de-orphaned. Studies showed that L-DOPA is the specific ligand for the OA1 receptor. L-DOPA is a by-product of melanin biosynthetic pathway. During melanin synthesis, L-DOPA is released to the retina in the retinal pigment epithelium and is necessary for specific stages of retinal development. Activation of the OA1 receptor by L-DOPA leads to the secretion of a neurotropic factor by the retinal pigment epithelium that helps in normal retinal development.
Mutations
The OA1 mutants were classified into two major groups based on glycosylation and localization patterns. While group I consisted of normally glycosylated OA1, group II represented aberrantly glycosylated OA1 which is indistinguishable from the wild type.
However, both these studies revealed that in >60% of these mutations, the protein was retained in the ER and which is assumed to be the major cause of OA1. They also revealed that the protein levels decreased drastically, probably due to misfolding of the protein in the ER. Some of the mutations reported in second and third cytoplasmic loops (these regions are known to be critical for GPCR downstream signaling) are believed to affect transduction of the signals from OA1 via G proteins.
Functions of OA1
Though the exact role of OA1 is yet to be confirmed, many studies give clues about the probable roles of OA1. The ''Oa1'' gene product might be involved in vesicular trafficking or sorting them to the melanosomes.
It is also believed to be involved in redistribution of mannose-6-phosphate receptors, thus suggesting that it is important for melanogensis.
Literature shows that it plays a major role in the final stages of growth and maturation of melanosomes. This conclusion is based on the fact that there are no intermediates of melanosome-melanosome fusion and the number of melanosomes decreases only on maturation of the cell and not in the initial stages of development. A number of genes in Drosophila, like the ''hook'' gene that alter ocular pigment granules have been shown to affect lysosomal delivery.
Moreover, it has been found that in normal conditions, melanosomal proteins traffic normally to late endosomes, while in the absence of OA1, they continue to accumulate in the mature melanosomes. This may mean that OA1 acts as a stop signal for melanosomal growth.
Pathophysiology
Microscopic examination of retinal pigment epithelium and skin
pigment cells (melanocytes) of people affected by ocular albinism type 1 reveal the presence of characteristic macromelanosomes, even though skin appears normal.
Studies from ''Oa1'' knock-out mice reveal that these giant
melanosomes
A melanosome is an organelle found in animal cells and is the site for synthesis, storage and transport of melanin, the most common light-absorbing pigment found in the animal kingdom. Melanosomes are responsible for color and photoprotection i ...
appear due to abnormal growth of a single melanosome and not due to aggregation or fusion of many melanosomes. These melanin macroglobules are probably formed due to failure of melanosomes to separate from the
ER-
golgi system with the accumulation of enzymes and other secretory proteins leading to an increase organelle size. However, Incerti, ''et al.'' contradict the above theory.
Diagnosis
Treatment
To date there is no treatment for ocular albinism, probably because little is known about the receptor function and its role in the pathophysiology of the condition. Though surgery for strabismus is sometimes helpful, there does not seem to be a sure remedy for it until the cause of ocular albinism is well established.
However, with the recent discovery of the upstream ligand (L-DOPA) and the discovery of Oa1's possible downstream G alpha partner (Gai3) the Oa1 pathway is becoming clearer and future of Oa1 research looks promising.
Touloukian ''et al.'' have characterized OA1 immunologically as a melanoma/melanocyte differentiation antigen.
[Shen, B., Rosenberg, B. and Orlow, S.J. (2001). Intracellular distribution and late endosomal effects of the ocular albinism type 1 gene product: Consequences of disease-causing mutations and implications for melanosome biogenesis. ''Traffic'' 2:202.] Flow cytometry data suggests that OA1-specific T cells are all CD8+. This indicates that OA1 peptide is processed and presented on the surface of melanoma cells to be recognized by antigen-specific T cells. Moreover, recognition of OA1 by T cells induces cytokine production by the OA1-specific T cells. This means that OA1 is a potential target for melanoma vaccines.
References
Further reading
GeneReview/NCBI/NIH/UW entry on Ocular Albinism, X-Linked
External links
{{DEFAULTSORT:Ocular Albinism Type 1
Amino acid metabolism disorders
X-linked recessive disorders
Eye diseases