Albinism Paper-Genetics perspective

Running head: [SHORTENED TITLE UP TO 50 CHARACTERS] 1

Albinism: The prevalence, stigma, and truth.

Shemuel Patton

Nevada State College

[SHORTENED TITLE UP TO 50 CHARACTERS] 2

Table of Contents

I. Introduction

II. Discussion

III. Summary

IV. References


Abstract

Albinism is the loss of melanin production within melanin producing cells, melanocytes. The

loss of melanin synthesis is due to certain mutations of particular genes on particular

chromosomes, the location and type of mutation of the gene determines the form of albinism

expressed. While albinism is a disease observed in several different ethnic populations, the types

of albinism expressed by individuals tend to be ethnically segregated. Research has also found

that the complexity and severity of particular types of albinisms depend upon particular

mutations occurring in conjunction with one another as well the inheritance patterns of the

mutated alleles. For oculocutaneous albinism type two (OCA2), the most prevalent and highly

mutated forms of albinism, becomes more severe when the "traditional" OCA2 gene is paired up

with another mutation that causes an alternative form of albinism; this is significant because

OCA1 is currently the most severe form of albinism do to the complete lack of pigmentation.

Keywords: Missense, phenotype, hypopigmentation, alleles, melanocytes,

phaeomelanosomes, eumelanosomes, frameshift mutation, truncation, consanguity


Albinism: The prevalence, stigma, and truth.

Albinism is a congenital disease that is unanimously characterized by poor vision and

variable pigmentation of the physical appearance, phenotype, of an individual (Montoliu, L. et. al

2013). Albinism is found in a variety of species, including but not limited to mice, vegetables,

scorpions, and reptiles; in this paper I will be focusing on albinism found within humans. There

are forms of albinism that are associated with specific mutations, some albinisms are caused by a

direct mutation in the gene responsible for the production of melanin. While there are some

albinisms caused by mutations of proteins, also known as missense mutation; missense mutation

is caused by the alteration of a single base pair nucleotide which alters the amino acid used and

ultimately the function of the resulting protein. Until recently, there was not much known about

albinism on the molecular level and its many forms expressed within species; with the

development of technology, there have been an increase in studies regarding albinism (Montoliu,

L et. al 2013). In fact, prior to the year 2007, scientists only knew of seven genes believed to

result in albinism but researchers are continuing to find that there are in fact several other genes

and proteins associated with albinism. The studies conducted have illuminated the molecular

processes occurring in individuals with albinism and have unearthed new causes (in regards to

mutations within genes and proteins) and ultimately new forms associated with the new causes.

Albinism is not a disease that appears to be solely endemic to a certain group of people, it

is a disease that has been observed and studied in several populations worldwide. However, as I

will discuss later in the paper, the form of albinism depends upon which genes or proteins have

been mutated; the genes associated with particular forms of albinism tend to be specific to

particular areas that people with these alleles reside. It has been observed and documented by


several researchers, particular forms occur at higher frequencies in certain ethnic groups while

the same form will occur at an abysmally low frequency in another ethnic group.

In this paper, I will discuss the most severe and common forms of albinism found within

populations and their associated genes that cause the specialized expression of albinism. While I

will not be covering albinism in the entirety of its forms due to the varying amounts of genes

responsible for the known eighteen forms of albinism, I would like to inform you that albinism

occurs in several forms and is the result of several mutations of genes on varying chromosomes.

I will also discuss the diseases and conditions people with albinism are more susceptible and

prone to acquire due to a severe lack of melanin producing cells, melanocytes. I will also briefly

elaborate on the social strata people with albinism experience within their societies in different

regions of the world. By the end of this paper, you will be informed about the genes that result in

varying forms of the most frequent types of albinism, the limited amount of treatments and

protective care for those with albinism, as well as the manner in which albinos are treated within

African societies.

Albinism-Society

Due to recent media coverage about the maltreatment experienced by albinos in

Tanzania, I decided to research where the acts of violence against albinos stem from in sub-

Sahara Africa.In sub-Saharan Africa people with albinism are said to be the result of witchcraft

due to someone within the family committing a wrongdoing against someone, which than placed

a curse of paleness upon resulting offspring. In Nigeria there is a city called Koho, and in Koho

the tribes believe that albinos are spirits, folklore states that albinos are unable to die a natural

death like humans and instead disappear like dust in the wind (Blankenberg, N. 2000).Similar to


other societies in under-developed regions, people within Koho society believe the mother is

solely at fault for producing an albino child; having an albino child within this society would not

only result in the mistreatment of the child but also the mother ( Lund, P. 2002).

In Zulu culture, one of the largest ethnic groups in South Africa, it is believed that

taunting or teasing of an albino person will result in an albino producing curse within their

family lineage. This fear and misunderstanding leads to the avoidance and ultimate isolation for

albino people, commonly referred to as Isishawa (the cursed), in Zulu culture (Blankenberg, N.

2000) .Reversely, in Soweto south Africa, albinos are treated kindly and with reverence because

the people attribute the paleness of skin to a direct connection to the spirit world. In Soweto

culture, giving birth or being born an albino increases one's social status significantly

(Blankenberg, N. 2000).

The purpose of this paper is to provide a scientific based explanation of albinism in light

of social stereotypes and stigmas. The most recently publicized being the increased mistreatment

of albinos in Tanzania, this mistreatment has been addressed by several local government

officials, UNICEF, and foreign governments that provide Tanzania financial assistance. The

reasons behind the mistreatment is due to the common, and often fatal, belief that albinos have

special "magical powers" and their organs contain these "powers" as well. Due to this

misconception , hair, internal organs, skin, and limbs are harvested to be used as talisman to

make people richer, more powerful, and prosperous in life (Cimpric, A. 2010). The Tanzanian

government in conjunction with UNICEF have embarked on a campaign to not only educate

Tanzanians but to also enhance the safety of albino individuals.


Albinism-Molecular level.

Albinism is a congenital disease that occurs world-wide with a frequency of 1/20,000

individuals ( Gargiulo, A et al 2011). It is characterized by poor vision and variable

hypopigmentation; people with albinism have a deficiency in the melanin pigment biosynthesis-

this reduction of melanin biosynthesis in melanocytes results in decreased amount of

pigmentation (Oetting 1996).The first form of albinism to be discussed is the severest known

type, oculocutaneous albinism; which effects the pigmentation of the skin, hair, and eyes. This

type is not similar to ocular albinism, which only effects the pigmentation of the eyes. Prior to

2007, it was believed that four genes and protein mutations caused oculocutaneous albinism in

humans, but with advancements of technology scientist have discovered that there are currently

seven known genes and protein mutations that cause oculocutaneous albinism (OCA); the

amount of gene and protein mutations appear to be expanding with the increase of research

focused on albinism. With the discovery of new genes, new forms of albinism are classified; this

increase of classification displays how diverse the disease is and the many forms it can be

expressed due to polymorphisms in genetic populations.

The first form of OCA is OCA1, OCA1 is caused by a frameshift mutation of the

tyrosinase gene (TYR).This gene mutation was first observed in a Japanese man and was also the

first mutation to be identified as causing albinism within humans; however OCA 1 is more

prevalent in European and Asian populations (Yuasa, I et al 2007). The frameshift mutation

suppresses enzymatic activity in the melanin biosynthesis pathway, the amount of melanocytes

may be unaffected but the ability to produce melanin in the melanocytes is affected by the TYR

gene mutation. Individuals with OCA1 are more susceptible to sunburns and skin cancers.

OCA1 can be characterized into two individual sub groups, the first being OCA1A; individuals


with OCA1A suffer from complete hypopigmentation, no melanin is able to be produced within

the melanocytes. Individuals with OCA1A lack pigmentation in their skin, hair, and eyes; the

lack of pigment in the eyes results in poor visual acuity.The second form of OCA1, is OCA1B

which is also caused by the mutation of the TYR gene but the mutation does not suppress

enzyme activity entirely and a minimal amount of melanin is able to be produced. Individuals

with this form of albinism are still characterized by pale skin, hair, and eyes but they have more

pigmentation in their eyes and hair than individuals with OCA1A (Manga, P et. al 2013). The

TYR gene is located on the eleventh chromosome and is one of two causes that hinder the

enzymatic production of melanin, the other cause is the tyrosinase related protein-1 (TYRP)

mutation located on the ninth chromosome.

The third form known as OCA3 (also referred to as rufous OCA) is caused by the

mutation of TYRP1; caused by the truncation of two exons found in the TYRP1 protein. The

truncation of these exons produce premature stop codons that produces a nonsense mutation; the

result if this nonsense mutation is the partial development of melanin. This form of albinism is

more frequent among south African populations and practically non-existent within Caucasian

populations; the allele frequency of this mutation is 1 in 8580 (Study of OCA and

vitiligo).Individuals with this form of albinism tend to develop pigmentation throughout their

lifetime and appear to have less ocular problems; researchers were able to study the melanocytes

of individuals with OCA3 and found that their melanocytes contain mature eumelanosomes and

premature phaeomelanosomes depending upon the stage of melanin production .The increase in

melanin (although slight) allows the retinal visual cells to develop properly because the synthesis

of melanin in the retinal pigment epithelium (RPE) is able to occur during development; in


OCA1 and OCA2, the absence or decrease of melanin altered the development of the visual cells

which results in poor vision(Manga, P. et. Al 2013)

The second form of OCA, OCA2 is the most prevalent form worldwide and within

African populations; within African populations OCA2 occurs at a frequency of 1/3900. OCA2

is caused by a mutation in the OCA2 gene, previously referred to as the P gene; OCA2 is located

on the fifteenth chromosome and is caused by a deletion in exon number seven but research has

found that transgenic deletions of exons 3-20 produce OCA2 as well (Ibarrola-Villava et. al

2010).The most common exon, seven, deleted codes for the ionic transport protein that is

responsible for the pH regulation of melanosomes (Oetting 1996). Recently researchers have

been studying the other frameshift, nonsense, and missense mutations that have been found to

produce OCA2; unfortunately due to recent discovery not much is known about the function of

the deleted exons but it is believed that they are responsible for the production transmembrane

proteins. Similar to OCA1,OCA2 can be separated into two subgroups: the first subgroup being

OCA2 which is characterized by hypopigmentation of varying degree, yellow to brown hair, pale

skin, and light colored eyes. The second subgroup is OCA2B, also known as brown albinism, is

characterized by light brown skin, beige to brown colored skin, and blue-green to brown colored

irises. Individuals with OCA2 and OCA2B produce pigmentation through their lifetime but are

still susceptible to sunburn, blistering, and freckling associated with sun exposure.

The fourth form, and one of the rarest forms worldwide is OCA4; OCA 4 is prevalent in

within Japanese populations. The mutation in the membrane-associated transporter protein gene

(MATP also referred to as the SLC45A2) caused by SNPs in one of the seven exons of the

MATP gene causes form OCA4. While researchers are unsure what role the MATP gene plays in

melanin synthesis, they believe one of the proteins produced in this gene is responsible for the


transportation of proteins necessary for melanin synthesis. The MATP gene was first discovered

in a Turkish man and has since been identified in German, Korean, and Japanese patients,

Researchers attribute the rareness of OCA4 is due to a founder chromosome found in a common

ancestor of Caucasians and Asian populations that occurred 15,000-35,000 years ago (Yuasa, I

et. al 2007).

The last three forms of OCA I will be discussing are the most recently discovered and

therefore the functions of genes are relatively unknown. OCA5 was discovered in a Pakistani

family and this form of albinism had a high occurrence of consanguity, consanguity in albinism

is not uncommon but the high occurrence of inheritability of the alleles was a novel discovery.

The gene, located on the fourth chromosome, that causes this form of albinism is unknown due

to the fact that this new form was discovered in 2012 and appears to occur in conjunction with

other forms of OCA. OCA6, discovered in 2013, was discovered in Chinese patients who

appeared to have autosomal recessive OCA but with varying degrees of hypopigmentation; this

form of albinism is characterized by light hair that darkens over time and iris transillumination

(Grønskov, K. et. al 2013). With further research, researchers found that this form of albinism is

the rarest form of OCA due to the low frequency of these recessive alleles in most populations.

The gene responsible for the expression of albinism is the SLC24A5, located on the fifteenth

chromosome, experiences a frameshift mutation and nonsense mutation that produces an amino

acid at a position that promotes the suppression of melanin biosynthesis The amino acids reduce

the number and size of melanocytes produced while also hindering the maturation of

melanocytes. Researchers also found that OCA6 can be caused by a deficiency in the production

of Hermansky-Pudlak syndrome protein altered the production of protein complexes that

ultimately interrupt the non-mutated SLC24A5 gene from producing melanosomes and the


biosynthesis of melanin; Hermansky-Pudlak syndrome is a form of syndromic albinism that can

be caused by several mutations on several chromosomes.

The last form OCA7, was discovered in 2013 and was first observed in a Denmark family

that was homozygous for the mutation. . Individuals with OCA7 had transillumination of the

irises (lack of pigment which makes the irises appear clear), reduced visual acuity,

nystagmus( rapid involuntary movements of the eyes), and chiasm misrouting of their optical

tracts (Gronskov et. al, 2013 ).OCA7 is caused by an nonsense mutation of the C10orf11 gene

located on the tenth chromosome,OCA7 is characterized by lighter pigmentation of the skin

(compared to unaffected relatives) and severe ocular problems. C10orf11 encodes for 198 amino

acid protein containing three leucine-rich repeats(LRRs) and one leucine-rich repeat C-terminal

domain(LRRCT), the LRRs and LRCT are responsible for the signaling and adhesion of

extracellular matrix assembly, neuronal development, and RNA processing of melanocytes

( Grønskov, K. et. Al 2013).

Problems and Treatments.

The common trait that characterizes albinism is visual problems in individuals;

individuals with albinism suffer varying forms of visual problems due to the decreased amount

of melanin that is required to form proper retinal pigmentation and photoreceptors (rods and

cones). This decrease in pigmentation results in foveal hypoplasia which is the

underdevelopment of the eye's internal surface, responsible for seeing detail.Individuals also tend

to have a reduced amount of retinal ganglion cells, a type of neuron, that are photoreceptors that

receive and decipher visual information received; in conjunction with increased sensitivity to

light and foveal hypolasia, individuals experience a very low visual acuity. Individuals with

albinism, mainly those with OCA, suffer from strabismus which is the misalignment of the eyes


and photophobia(a sensitivity to light); the misalignment can be corrected with surgery but the

surgery rarely improves the visual acuity of the individual ( Tavakolizadeh, S et. Al 2011).

Individuals with albinism also have a higher susceptibility to skin cancers due to

hypopigmentation, while individuals are prone to blistering, freckling, and melanoma; melanoma

is the most dangerous form of skin cancer that is a result of UV damage to skin cells and

produces cancerous tumors. Since OCA has prevalence of 1 in 1000 in sub-Saharan Africa,

researchers have been discovering ways to protect individuals from skin cancers and provide

health information to affected individuals and their families. Researchers and health workers

suggest those with OCA wear photo-protective clothing, such as hats with wide brims, long

sleeve garments, protective eyewear, and broad spectrum sunscreen; the implementation of such

measures in sub-Saharan Africa need to be proposed by physicians because these measures are

not needed by the majority of the population and are therefore viewed with minimal regard

(Photochemistry and albinism). Researchers and health workers also suggest that individuals

with OCA utilize natural shade but also created shade, either from umbrellas or structures built to

protect children and individuals from excessive sun exposure; unfortunately such structures are

not frequent in southern Africa but the frequency of them would potentially protect several OCA

individuals from excessive sun damage.

Lastly, there are not many treatments available or discovered for individuals who suffer

from hypopigmentation, the main reason being there are several causes and mutations that cause

the phenotypic expression of albinism. The increase of mutations makes treating albinism as one

disease difficult because many factors are involved and can not be remedied the same as a

different factor. However, scientists believe that tracking the mutations and understanding the

role the mutated gene plays in the production of melanin will allow for effective treatments to be


created and implemented; meaning if a patient is known to express albinism due to a mutation of

one gene, such as tyrosinase (TYR), the patient can undergo treatments that facilitate the increase

of TYR activity in melanocytes. Creating effective treatments for less variable types of albinism

will be easier to produce but will prove difficult for the more variable types of albinism, but gene

therapy for individuals with albinism becomes more likely with continued research and studies.

Conclusion.

Despite the fact that I focused on the most prevalent and severe non-syndromic forms of

albinism, I again wish to reiterate that there are currently a total of eighteen different forms of

albinism. Seven of which I discussed throughout this paper and the other ten forms tend to be

less prevalent within populations but also have a larger variety of gene mutations contributing

and causing these particular syndromic forms of albinism. The eighteenth form is ocular

albinism, and tends to be more frequent within males because it is an X-linked disease; while the

syndromic albinisms and ocular albinism are important forms of the disease the molecular

processes of this diseases were beyond the scope of this paper due to the sheer complexity of the

biosynthesis and underlying factors. Understanding the biosynthesis and roles of the genes that

cause oculocutaneous albinism allows researchers to better understand the syndromic forms of

albinism and use the discovered information as a template for exploring the syndromic forms.

Albinism is a complex disease that effects all ethnicities to varying degrees based upon

inherited forms from parents or forms caused by mutations during development. There are

several genes responsible for the expression of albinism and several mutations can occur within

one gene to produce a variant form of a type of albinism, this variation in mutations prevents

diagnostic screening from being as effective as it is in other diseases where there are not several

variables. Diagnostic screening and treatments are possible for "simple" forms of albinism that


possess expected gene mutations, although scientists are discovering that the "simple" forms of

albinism are not as simple as previously assumed. With the increase of polymorphisms in alleles

and the sharing of once isolated alleles are giving rise to more complex forms of albinism;

despite this challenge, several researchers continue to dedicate their career to unraveling the

mystery behind albinism and hopefully provide forms of treatments for those with the disease.

Until treatments are available, those with albinism should wear longer garments to protect their

skin from ultraviolet radiation that could result in skin cancer, lesions, blistering, and freckling.

The necessity to regularly apply broad spectrum sunscreen and wear protective eyewear and

garments should be addressed by doctors, especially within societies where such preventative

measures normally do not need to be taken. Addressing these needs would not only increase the

overall health of an albino individual but would also reduce the stigma associated with having

fairer skin; providing accurate and scientific reason behind this disease would educate those with

albinism as well as those who are misinformed about albinism.

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Albinism Paper-Genetics perspective