August 18, 2015
Years published: 2008, 2012, 2015
NORD gratefully acknowledges William S. Oetting, PhD, School of Pharmacy, Department of Experimental and Clinical Pharmacology and College of Biological Sciences, Department of Genetics, Cell Biology and Development, University of Minnesota, for assistance in the preparation of this report.
Ocular albinism type I (OA1), or X-linked ocular albinism, is the most common form of ocular albinism. Ocular albinism is a genetic disorder characterized by vision abnormalities in affected males. Vision deficits are present at birth and do not become more severe over time. Affected individuals have normal skin and hair pigmentation. Ocular albinism is inherited as an X-linked recessive genetic condition and caused by mutations in the G protein-coupled receptor 143 (GPR143) gene.
Ocular albinism primarily affects pigment production in the eyes. Several vision problems can occur with ocular albinism including an involuntary movement of eyes back and forth (nystagmus), reduced iris pigment in some individuals, reduced retinal pigment, lack of development of the fovea (foveal hypoplasia) leading to blurred vision, and abnormal connections in the nerves from the retina to the brain that prevents the eyes from tracking together and reduces depth perception. Crossed eyes (strabismus) and sensitivity to light (photophobia) are also common. Typically individuals have normal hair and skin pigmentation.
Congenital motor nystagmus is a genetic condition characterized by an involuntary movement of eyes back and forth (nystagmus). Affected individuals will often turn or bob their head to try to improve vision clarity. Pigmentation in the eye is normal. There is preliminary evidence that some mutations of GPR143 result in X-linked congenital nystagmus in males. This has been seen in several different Chinese families. Affected males have congenital nystagmus but they do not have the additional changes typically seen in individuals with classical X-linked ocular albinism including a reduction in retinal pigmentation and pathological changes to the fundus. Female carriers appear to be unaffected. Further research needs to be done to understand how mutations in the same gene can result in different outcomes.
Mutations in the G protein-coupled receptor 143 (GPR143) gene on the X chromosome encoding a protein of 404 amino acids and are associated with ocular albinism type I (OA1). This protein is expressed in the retinal pigment epithelium (RPE) of the eye and melanocytes. GPR143 interacts with the premelanosomal protein MART1 which also plays a role in the regulation of melanin pigment formation. MART1 may act as a chaperone protein for GPR143. Mutations in GPR143 result in enlarged aberrant premelanosomes with aberrant fibril formation. There is also a decrease in melanin pigment synthesis in the premelanosome. The premelanosome is the intracellular location of melanin pigment production in the pigment cell. Aberrations of melanosomes in the skin are also present, but do not seem to reduce the amount of skin and hair pigment. GPR143 is also thought to be a receptor for L-DOPA (L-3,4-dihydroxyphenylalanine), an intermediate metabolite in the melanin pigment pathway, and may be involved in intracellular signaling in the retina.
Most mutations associated with OA1 have been missense mutations, but nonsense, frameshift and splice site mutations have also been reported. Several large deletions including one or multiple exons have also been reported. In some cases flanking genes such as SHROOM2 may also be involved, but these additional genes have not been shown to be associated with alterations in pigmentation but could be involved in ocular albinism type 1 syndrome.
Ocular albinism is inherited as an X-linked recessive genetic condition. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and most of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because inactivation of the X chromosome is random and usually half of the cells in the eye have the normal X chromosome activated resulting in normal vision. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
The prevalence of ocular albinism has been reported to be one male in 20,000 births.
The diagnosis of ocular albinism is based on the characteristic eye findings. Female relatives who carry the gene for ocular albinism will have some retinal pigment abnormalities (seen as mild iris transillumination) but usually will not have the visual changes observed in affected males. Very rarely females can be affected with the hallmarks of OA1 including nystagmus and foveal hypoplasia with reduced visual acuity. Molecular genetic testing for GPR143 gene detects mutations in approximately 90% of affected males and is available to confirm the diagnosis.
Individuals diagnosed with ocular albinism should be evaluated by an ophthalmologist at the time of diagnosis to determine the extent of the disease and have ongoing ophthalmologic examinations annually. Glasses or contact lenses can greatly improve vision. Dark glasses or a hat with a brim can help to reduce sun sensitivity (photophobia).
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