Oculocutaneous Albinism
Oculocutaneous Albinism, commonly referred to as OCA or simply Albinism, is a genetic disease that affects approximately 1 in 17000 people worldwide.
People with OCA are born with white hair, including eyebrows and eyelashes, and whitish-pink skin. Depending on the type of OCA, affected people may stay unpigmented for the rest of their lives or gain some degree of pigmentation in later years. Aside from white hair and skin, people with OCA also have less or no pigmentation in their eyes and often suffer from poor vision and other eye abnormalities.
OCA is an autosomal recessive disorder, which means both parents must carry the mutated gene and pass it on for their child to develop the disease.
There are multiple different types of OCA. OCA1 has a prevalence of about 1 in 40,000 people and is most common among Caucasians. There are two subtypes of OCA1, OCA1A and OCA1B. OCA1A is the most severe of all OCA types and is characterized by the complete absence of pigmentation all throughout life. OCA1B on the other hand, presents with varying degrees of pigmentation that develop later in life. The same is true for OCA2-OCA7. The most common form of OCA is OCA2 with a prevalence of about 1 in 36,000 people and is mostly found in Africa. OCA3 is also most common in African countries and very rare in Caucasians. OCA4 has a very high prevalence in Japan but can be found in other countries as well. OCA5-7 are extremely rare and will not be covered in this video.
Before we dive into genetic differences between different types of OCA, let’s cover some background information to understand what exactly happens in people with albinism.
The main characteristic, or phenotype, people with OCA present with is the absence or reduction of pigmentation. Specifically, this means affected people produce little or none of the pigment called melanin. Melanin is produced in a special cell type called melanocytes and within melanocytes, melanin is produced in the cell compartment, or organelle, called melanosome.
To better understand this, cell types can be compared to companies. Companies usually consist of many departments that all have their own functions and responsibilities to make sure that the company runs smoothly. In cells, these different departments are called organelles. Just like many companies share the same departments, let’s say a finance department, most cell types have the same organelles, such as the nucleus for example. However, more specialized companies may have departments that other companies don’t have. Similarly, special cell types have organelles that other cell types don’t have. The melanosomes within melanocytes are one example of specialized organelles within special cell types.
So, now we know that the missing pigment in OCA is called melanin and it is produced in melanosomes within melanocytes. Melanocytes can be found in our skin, hair, eyes, and inner ear. All of this explains the phenotypes of whitish-pink skin, white hair, and red or translucent eyes.
Other than just providing pigmentation, melanin is important to protect our bodies from DNA damage caused by UV radiation. DNA damage caused by UV radiation can lead to skin cancer and death. Melanin serves as a shield of protection against UV radiation by scattering and absorbing it.
Even with normal melanin production, prolonged exposure to sunlight leaves us at a high risk of DNA damage. People with OCA don’t have the protective shield of melanin to prevent DNA damage and completely rely on the ability of their cells to repair any DNA alterations. Although our cells are equipped with a special machinery that constantly scans our DNA for damage, this machine is not without its faults and the more damage occurs, the higher the risk that the DNA repair machine misses it.
For that reason, people with OCA are at a particularly high risk of skin cancer compared to the rest of the population.
Now that we know what’s behind pigmentation and how important it is, what are the genetic differences between different types of OCA and how do they lead to a lack or reduction of pigmentation?
OCA1 results from a mutation in the TYR gene which carries the information for a protein called tyrosinase. The TYR gene is located on the long arm of Chromosome 11. Over 300 different mutations of the TYR gene are currently known. Parents don’t need to have the exact same mutation in order to inherit OCA1. As long as they have any mutation in the TYR gene that renders the protein less or non-functional, the disease will develop. This means that depending on the kind of mutation, the affected person has either a completely non-functional or a partially functional tyrosinase protein. Non-functional tyrosinase proteins lead to OCA1A, the most severe form of OCA that is characterized by complete absence of pigmentation. Partially functional tyrosinase proteins lead to OCA1B, which shows varying degrees of pigmentation depending on the functionality of the tyrosinase protein.
The tyrosinase protein is located within the membrane of melanosomes. It has a small region that faces the cytoplasm of the melanocyte and a larger region that faces the inside of the melanosome. On the inside of the melanosome, the tyrosinase protein catalyses the first two chemical reactions that transform tyrosine to melanin. If the tyrosinase protein is inhibited or non-functional due to mutations, the production of melanin is reduced or abolished.
In OCA2 the affected gene is called OCA2 gene, sometimes still referred to as the P gene. The OCA2 gene is located on the long arm of Chromosome 15 and encodes for the P protein, also known as melanocyte-specific transporter protein. Over 100 mutations are known in the OCA2 gene to date. None of these mutations lead to a complete lack of pigmentation as seen in OCA1A. Instead OCA2 presents with varying degrees of pigmentation similarly to OCA1B. The exact function of the P protein is currently unknown. However, it is thought that the P protein is involved in transporting proteins to the melanosome, stabilizing melanosomal protein complexes, and regulating the melanosomal environment.
OCA3 is caused by mutations in the TYRP1 gene which is located on the short arm of Chromosome 9. Only about 16 mutations are known of the TYRP1 gene. The TYRP1 gene carries the information for a protein called tyrosinase-related protein 1. The function of this protein is to stabilize the tyrosinase protein. Mutations within the TYRP1 gene lead to non-functional or inhibited TYRP1 proteins and early degradation of the tyrosinase protein. This results in reduced levels of melanin production, which explains the low pigmentation levels of people with OCA3.
People with OCA4 carry mutations in the SLC45A2 gene, also known as MATP gene, which is located on the short arm of Chromosome 5. So far, 78 mutations of the SLC45A2 gene are known. The SLC45A2 gene codes for a protein called membrane-associated transporter protein, or MAPT protein. Not much information is known about this protein other than that it is located in the melanosomal membrane and it is essential for melanin synthesis. Similarly to other OCA types, mutations in the SLC45A2 gene result in reduced melanin synthesis and the phenotypic reduction in pigmentation of OCA4 patients.
What does all of this mean with regard to a prognosis for people diagnosed with OCA? There is no cure for OCA, but luckily, life expectancy for people with OCA is comparable to the rest of the population. However, there is an increased risk for skin cancer and necessary precautions must be taken to avoid unprotected exposure to sunlight. Treatments for eye abnormalities are available and neither intelligence nor fertility in OCA patients are affected in any way.
Literature used
OCA
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857599/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211462/
https://www.ncbi.nlm.nih.gov/books/NBK519018/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100393/
Tyrosinase protein
https://pubmed.ncbi.nlm.nih.gov/11041207/
Melanin and UV radiation
