Oculocutaneous Albinism

What is Albinism?

The eyes of those with OCA1A (subtype of OCA1) feature pink, almost translucent irises 1. OCA1A is the most severe form of oculocutaneous albinism and features very little to no melanin production in the melanocytes of the hair, skin, or eyes 1.

Albinism is an autosomal recessive disorder caused by either a partial lack or complete lack of melanin biosynthesis 1. Autosomal recessive disorders are disorders that are caused by genes located on a numbered, non-sex chromosome 2. Sufferers of autosomal recessive disorders must inherit two defective (recessive) copies of a gene to have the disease 2.

What is Melanin?

Melanin is a term for a group of molecules produced in the body that are responsible for biological functions such as pigmentation and photoprotection 4 . There are three forms of melanin in humans: eumelanin (brown pigmentation), pheomelanin (yellow, reddish pigmentation), and neuromelanin which is in the brain and unrelated to the ectoderm melanin's of eumelanin and pheomelanin 4 . Following the neural tube closure in embryonic development, melanoblasts migrate from the neural crest and become melanocytes 4. Melanocytes produce melanin which is packaged in melanosomes and transported to keratinocytes where they offer photoprotection 4.

Autosomal recessive inheritance pattern of albinism3

Who is Affected by Albinism?

Albinism impacts mammals, amphibians, birds, fish, and reptiles 11. The disease is characterized across all those affected by hypopigmentation in the eye alone, or in the eyes, hair and skin together 11. All humans impacted by albinism have abnormalities in their optic systems characterized by incorrect connections of optic fibers between the retina and brain 11. Incomplete development of the fovea is also observed 11.

The image above shows an experiment conducted on zebrafish which can be a model organism used to study albinism 12. From left to right the fish go from no albinism induced to the most albinism induced 12.

Types of Albinism

What causes Albinism?

Tyrosinase mediated production of Eumleanin and Pheomelanin 6

Albinism is caused by mutations in varying genes associated with melanin production 1. Clinically, the various forms of albinism can oftentimes be indistinguishable and can only be differentiated by molecular analysis to determine which gene is mutated 1. It’s these different gene mutations that cause the different types of albinism 1.

Type

OCA1 (1A and 1B)

There are two well known mutations that cause OCA1A, the first being a SNP change where a cytosine is changed to an adenosine in exon 3 of the TYR gene 5. This change disrupts the glycosylation motif of Tyrosinase, results in misfolding, endoplasmic reticulum retention, degradation, and complete loss of enzymatic activity 5. The second mutation that results in OCA1A is a mutation of a guanine to an adenosine in exon 1, this causes structural instability in the N-terminal region and loss of Tyrosinase activity 5. In OCA1B there are multiple mutations that can cause a decrease, but not complete loss of Tyrosinase activity including 5. The primary difference between the two subtypes of OCA1 being the 1A type results in a complete loss of Tyrosinase activity while 1B results in only a partial loss of Tyrosinase activity 5.

OCA2

OCA2 is the most common form of albinism 1. Two mutations are associated with OCA2, a missense mutation and in-frame deletion mutation 7. OCA2 does not result in complete inactivity of Tyrosinase, therefore individuals affected by OCA2 can accumulate pigment over time 1.

OCA3

OCA3 is a more recently established, distinct form of albinism 8. Mutations on the TRP-1 gene cause this form 8. The mutation causes reduced tyrosinase activity, and a failure to synthesize black eumelanin leading to the brown phenotype of albinism seen in people of African descent 8. TRP-1 stabilizes tyrosinase 8.

OCA4

OCA4 is characterized by mutations which impact the SLC45A2 gene (also known as (MATP) 9. SL45A2 is a gene which encodes a protein called NCKX5 which is a sodium/potassium/calcium exchanger involved in transporting ions across melanosomes 10. This transporter helps regulate pH levels in melanosomes which controls Tyrosinase activity and impacts which type of melanin is produced (eumelanin, pheomelanin) 10. This gene is also responsible for a significant portion of the lighter skin seen in non-African peoples 10. Mutations in this gene lead to a dysfunctional NCKX5, and diminished tyrosinase activity 9.

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