Albinism is a group of genetic disorders which is characterized by lower quantities or an absence of melanin pigmentation. Albinism occurs with a frequency of about one per 20,000 in most populations. Albinism can be subdivided into oculocutaneous albinism (OCA) which affects the eyes, skin, and hair versus ocular albinism (OA), which affects vision and is accompanied by some degree of reduced segmentation of the skin on the hair.
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It is estimated that while the global prevalence is ~1 in 20,000, worldwide, prevalence rates vary. In Australia, the ratio is approximately 1 in 17,000, and in Zimbabwe, the prevalence is approximately 1 in 1,000.
What are autosomal recessive traits?
Albinism is inherited in an autosomal recessive manner. This means both copies of a gene in each cell have mutations. For an individual with albinism, approximately one in four of their siblings will also present with albinism. Recessive inheritance is characterized by the following properties:
- Both copies of the gene must be defective to cause the phenotype
- The presence of a secondary copy can compensate for a defective copy; This is because two alleles comprise one gene pair
- The cell can tolerate reduced levels of a gene product
- Male and females are affected equally
- Affected individuals Will have little to no family history
- Carriers are unaffected but may show minor aspects of the phenotype
- If one parent is affected and the other parent is a heterozygotes carrier for the same gene then 50% of the children will be affected
- if both parents are affected and defective for the same gene, then all children will be affected
- the risk to one child is independent of whether their siblings have the trait
How pigmentation is affected
There are two main forms of melanin, called eumelanin, and the ratio between these two types of pigment, which affect skin tone, depends on the genetic background of a person. This, in turn, is determined by parental inheritance.
Melan is a dark pigment that is responsible for brown to black pigmentation and is the most common of the two. Pheomelanin is responsible for yellow to red hues in hair, skin, and lips.
Genetic mutations involved in albinism
Genetically, albinism is classified according to the type of genetic mutation present. There are seven types of nonsyndromic OCA identified to date:
Type 1 OCA and type 2 OCA are the most common; OCA1 is considered to be the most prevalent type across the world affecting ethnic groups add characterized by the loss of function of the tyrosinase enzyme. This is caused by a mutation in the TYR gene. Tyrosine catalyze is a critical step in the biosynthesis of the brownish-black eumelanin and yellow pheomelanin.
Individuals with OCA1A genotypes have nonfunctional tyrosine with a total absence of melanin production. Individuals with OCA1B have some functional tyrosine activity with a limited production of melanin.
OCA2 Is the most prevalent form of albinism in Africa. The prevalence of OCA2 is markedly higher than the European population and is characterized by a mutation in a gene which in codes the P protein.
The exact function of the P protein is not fully understood, but it appears to be involved with the transport of proteins to melanosome, stabilizing the melanosomal- protein complex and regulation of the pH of them melanosome and/or metabolism of glutathione. All of these activities are key for melanin production. More than 140 mutations have been identified in its gene body.
The type 3 phenotype of albinism is caused by mutations in genes that encode the tyrosinase-related protein 1 (TYRP1). Type 4, OCR4, is caused by a mutation in the membrane-associated transporter protein (MATP). TYRP1 is responsible for the stabilization of tyrosine and mutations in TYRP1 are associated with early degradation of the enzyme and late maturation of melanosomes.
MATP functions as a melanosomal membrane transporter protein which is necessary for the biosynthesis of melanin. Mutations in MATP cause hypopigmentation.
OCA5 is linked to a specific, but unidentified gene mapped to the region of the 4q24 chromosome. which was discovered in members of a Pakistani family descended from the same ancestor (consanguineous)
The molecular basis of albinism
In 2013, a team of Chinese researchers reported the use of exome sequencing to reveal the molecular basis of albinism in an affected family. This Chinese research team discovered mutations in SLC24A5, a gene that encodes a solute transporter protein that was associated with a new form of OCA, OCA6. It belongs to a family of potassium-dependent sodium/calcium exchangers which are implicated in the maturation of melanosomes.
These mutations were detected in patients of multiple ethnicities which indicated that this form of OCA is not restricted to a Chinese population. More recent results indicate that SLC24A5 is responsible for the maturation of melanosomes, melanosomal architecture, and the biosynthesis of melanin.
Alongside SLC24A5, the C10orf11 gene was identified using gene mapping of a consanguineous family from Lithuania; this is referred to as OCA7. The open reading frame of this gene encodes a protein, 226 amino acids in length. Although the function of the protein is unknown, it is believed to play a role in melanocyte differentiation.
Further understanding of the pathological mechanisms that underlie syndromic and nonsyndromic OCA will allow comprehensive genetic screening and diagnosis to take place. Through further investigation including an understanding of intracellular trafficking, and the functions of the proteins and transporters involved in melanin production may help inform improvements in the cat of patients with both syndromic and non-syndromic OCA.
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- Yang Q, Yi S, Li M, et al. (2019) Genetic analyses of oculocutaneous albinism types 1 and 2 with four novel mutations. BMC Med Genet. doi:10.1186/s12881-019-0842-7.
- Fernández A, Hayashi M, Garrido G, et al. (2021) Genetics of non-syndromic and syndromic oculocutaneous albinism in human and mouse. Pigment Cell Melanoma Res. doi:10.1111/pcmr.12982.
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