Biology and genetics of oculocutaneous albinism and vitiligo - Common pigmentation disorders in southern Africa

Abstract

Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism (OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of disorders that result in hypopigmented skin due to decreased melanin production in melanocytes and loss of visual acuity. There are four non-syndromic forms, OCA1-4, which are classified based on the gene that is mutated (tyrosinase, OCA2, tyrosinase-related protein 1 and SLC45A2, respectively). Despite the fact that multiple genes account for the various forms of OCA, the phenotypes of all four forms result from disruption in the maturation and trafficking of the enzyme tyrosinase. OCA2 is the most prevalent autosomal recessive disorder among southern African blacks, affecting 1/3 900 individuals; while OCA3, although rare, is most prevalent in southern Africa. Another common pigmentation disorder in southern Africa is vitiligo, which affects 1 - 2% of people worldwide. Vitiligo is a complex, acquired disorder in which melanocytes are destroyed due to an autoimmune response. The aetiology underlying this disorder is poorly understood, although recent genetic association studies have begun to shed light on the contributing factors. Pigmentation disorders have significant psychosocial implications and co-morbidities, yet therapies are still lacking. Recent progress in our understanding of the pathobiology of both albinism and vitiligo may herald novel treatment strategies for these disorders.

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Biology of pigmentation
The primary pigment that determines human skin,
hair and eye colour is melanin, which is synthesised
by melanocytes. Melanin protects the skin from
ultraviolet (UV) radiation and there is an inverse
correlation between the degree of constitutive pigmentation and the
risk of sun-induced skin cancers. Besides the life-threatening cancer
risk, loss of pigmentation results in premature aging, compromised
cutaneous immunity and significant emotional distress to affected
individuals.[1-3]
During embryonic development, melanocyte precursors that
arise from the neural crest populate several areas including the
interfollicular epidermis and hair follicle bulge in the skin; the uveal
tract of the eye; and the stria vascularis, vestibular apparatus and
endolymphatic sac of the ear. The development of melanocytes is
tightly regulated at the genetic level by a number of genes that control
proliferation, survival and migration of precursor cells to the various
sites of the body and their differentiation into active melanocytes.
A key regulator of this process is the microphthalmia transcription
factor (MITF), which has been dubbed the ‘master regulator’ of the
melanocyte, capable of modulating expression of several melanocyte-
specific proteins.[4] MITF mutations result in Waardenburg syndrome
type II.[5] Once the melanocyte has differentiated, MITF regulates
expression of genes in response to UV exposure, facilitating the
tanning response.
Melanocytes produce two forms of melanin, black-brown
eumelanin and red-yellow pheomelanin. Skin and hair colour
Biology and genetics of oculocutaneous albinism and vitiligo
– common pigmentation disorders in southern Africa
P Manga, PhD; R Kerr, PhD; M Ramsay, PhD; J G R Kromberg, BA (Soc Work), MA, PhD
P Manga is at e Ronald O Perelman Department of Dermatology and the Department of Cell Biology, New York University School of Medicine,
New York, USA. J G R Kromberg, M Ramsay and R Kerr are at the Division of Human Genetics, University of the Witwatersrand and National
Health Laboratory Service, Johannesburg, South Africa.
Corresponding author: P Manga (prashiela.manga@nyumc.org)
Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism
(OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of
disorders that result in hypopigmented skin due to decreased melanin production in melanocytes and loss of visual acuity. There are four
non-syndromic forms, OCA1-4, which are classified based on the gene that is mutated (tyrosinase, OCA2, tyrosinase-related protein 1 and
SLC45A2, respectively). Despite the fact that multiple genes account for the various forms of OCA, the phenotypes of all four forms result
from disruption in the maturation and trafficking of the enzyme tyrosinase. OCA2 is the most prevalent autosomal recessive disorder
among southern African blacks, affecting 1/3900 individuals; while OCA3, although rare, is most prevalent in southern Africa. Another
common pigmentation disorder in southern Africa is vitiligo, which affects 1 - 2% of people worldwide. Vitiligo is a complex, acquired
disorder in which melanocytes are destroyed due to an autoimmune response. The aetiology underlying this disorder is poorly understood,
although recent genetic association studies have begun to shed light on the contributing factors. Pigmentation disorders have significant
psychosocial implications and co-morbidities, yet therapies are still lacking. Recent progress in our understanding of the pathobiology of
both albinism and vitiligo may herald novel treatment strategies for these disorders.
S Afr Med J 2013;103(12 Suppl 1):984-988. DOI:10.7196/SAMJ.7046
Prashiela Manga joined the Department of Human Genetics at
the University of Witwatersrand in 1991 as an Honours student
and went on to complete a PhD in 1997. Both her projects focused
on mapping genes involved in albinism. Her fascination with the
biology of pigmentation was fostered by her mentors and co-authors
on this review, MR and JK, and in no small part by interactions and
discussions with Trefor Jenkins. PM’s laboratory at the New York
University School of Medicine continues to focus on unravelling
the mechanisms involved in regulation of skin pigmentation and
elucidating the pathobiology of various pigmentation disorders.
Jennifer Kromberg worked with Trefor Jenkins in his Department
of Human Genetics from 1971 to 1999 and again later in the same
department, as a retiree, from 2005 to date. As a social scientist
she undertook both MA and PhD studies on the psychosocial and
genetic aspects of oculocutaneous albinism, and has published
many papers on the topic. During the early 1990s the albinism
work required a molecular approach and this work was primarily
guided by Michele Ramsay who had recently returned following a
postdoctoral fellowship in London. Four molecular PhD projects
on albinism were completed by students in the department: Mary-
Anne Kedda (nee Colman), Gwyneth Stevens, Prashiela Manga and
Robyn Kerr. All four have proceeded with careers in science and
Robyn Kerr is currently an academic member of the Division. It is
a great pleasure to write this review for the Festschrift in honour of
Trefor Jenkins’ remarkable academic career.

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is determined by the total amount and ratio of eumelanin to
pheomelanin. Melanogenesis occurs within membrane-bound
organelles known as melanosomes. This limits the potential for
cellular damage by the intermediates of melanin synthesis, which
include reactive oxygen species. Melanosomes consist primarily of
proteins that are synthesised in the endoplasmic reticulum (ER) and
are then routed to the melanosome either directly or via the Golgi
where additional modifications, such as glycosylation, are made to
the protein.
Mutations in a host of genes have been described that result in
the failure of protein delivery to the melanosome. The majority of
these comprise the various forms of Hermansky-Pudlak syndrome.
To date, at least nine forms have been described, each due to
mutations in a different gene. In addition to oculocutaneous albinism
(OCA), affected individuals lack platelet-dense bodies, causing a
bleeding diathesis, and can experience granulomatous colitis or fatal
pulmonary fibrosis.[6]
Once the key enzymes, including tyrosinase, and structural
proteins have been delivered, melanin synthesis begins. Melanin
fills the melanosome, which is transported to the dendrites of the
melanocyte and is eventually transferred to the keratinocytes where
it forms a nuclear cap that protects DNA from UV-induced damage.
In white skin, melanosomes are small, not very heavily pigmented
and form membrane-bound clusters in the keratinocytes that are
eventually degraded generating ‘melanin dust’ in suprabasal layers
of the skin.[7] In black skin, melanosomes are large and remain as
single organelles throughout the skin, while both forms are found
in Asian skin.[8]
Over a hundred genes are thought to play a role in melanin
synthesis and melanocyte function; however, only 11 have been
confirmed as key determinants of normal skin pigment variation
through genome-wide association studies to date,[9] with some genes
linked exclusively to either inter- or intra-population variation. Fewer
genes have been implicated in determining hair and eye colour, with
the melanocortin-1 receptor (MC1R) shown to be the ‘red hair’
gene[10] and OCA2 the ‘brown eyes’ gene.[11]
OCA
OCA denotes a group of common autosomal recessive disorders
resulting from disruption of melanin synthesis. There are four major
forms: (i) OCA1 (mutated tyrosinase (TYR) gene);[12] (ii) OCA2
(mutated OCA2 gene);[13] (iii) OCA3 (mutated tyrosinase-related
protein 1 (TYRP1) gene);[14] and (iv) OCA4 (mutated solute carrier
family 45, member 2 (SLC45A2) gene).[15] OCAs are characterised
by decreased or absent melanin in skin, hair and eyes. Lacking
photoprotection provided by melanin, individuals with OCA are
highly susceptible to skin cancers, particularly squamous cell
carcinoma.
A loss of visual acuity is also a consequence of OCA. During
development, decreased melanin synthesis in the retinal pigment
epithelium results in foveal hypoplasia and dysregulation of adjacent
retinal ganglion cells, and consequently, misrouted decussation of the
nerve fibres connecting the retina to the brain at the optic chiasm.
Melanin also plays a role in the adult eyes where it is important
for reducing light scatter and improving acuity. Individuals with
OCA thus experience nystagmus, strabismus and photophobia. A
significant number of children in southern African schools for the
blind suffer from OCA.
In addition to the physiological issues, the highly visible nature
of the OCA phenotype, particularly in black communities, causes
significant psychosocial co-morbidities. These include maternal
rejection in infancy,[16] later adjustment problems and stigmatisation
due in part to the widely believed death myth that people with
albinism do not die normal deaths, but disappear at the end of their
lives.[17] A study of Nigerians with OCA2 found that they experienced
alienation, avoided social interactions and were less emotionally
stable. Furthermore, affected individuals were less likely to complete
schooling, find employment and find partners.[18]
Albinism occurs at high frequencies in populations of African
origin. OCA2 is particularly common, with a few mutations
accounting for most cases, suggesting a shared genetic history.[20]
Several factors may have contributed to the retention of albinism-
causing mutations: (i) carriers with lighter skin are considered more
suitable mates; (ii) fertility advantage; and (iii) carrier advantage such
as reduced susceptibility to disease (e.g. lighter skin may result in
fewer mosquito bites and a reduced risk of malaria).
Molecular and biochemical basis
The biochemical basis of albinism was first speculated by Garrod
in 1908 as an inborn error of metabolism.[19] He correctly theorised
that the phenotype was due to the absence of enzyme activity. The
enzyme in question is tyrosinase, the key melanogenic enzyme
that catalyses the first biosynthesis reaction converting tyrosine to
L-3,4-dihydroxyphenylalanine (L-DOPA). The maturation process
required to generate a functional tyrosinase enzyme is complex and
highly regulated. Maturation begins in the ER where chaperones
facilitate folding, post-translational modification and acquisition
of tertiary structure. Further modifications are made in the Golgi
before tyrosinase is transported to melanosomes. Mutations that
result in OCA1-4 all result in retention of tyrosinase in the ER and/or
misrouting that prevents delivery to the melanosome. One approach
to promote tyrosinase maturation in melanocytes in culture is to
increase the levels of tyrosine or L-DOPA, which accounts for an
early observation, prior to genetic classification of albinism, that
hairbulbs incubated in high levels of tyrosine could indicate whether
the type of OCA was tyrosinase-negative (no increase in melanin) or
-positive (heavily pigmented hairbulbs post incubation).
OCA1
OCA1 is an autosomal recessive disorder caused by TYR mutations.
To date, more than 100 mutations have been described at this locus.
OCA1 has been reported throughout the world and occurs with a
frequency of about 1/40000 worldwide, with the highest prevalence
in white populations.[12] It is extremely rare in black populations.[21]
OCA1 presents at birth with a range in severities. The most severe
phenotype, OCA1A or tyrosinase-negative albinism, results from a
complete lack of enzyme activity and pigment remains completely
absent in the skin, hair and eyes throughout life. Hypopigmentation is
accompanied by a severe ocular phenotype. Milder mutations encode
proteins with some residual enzyme activity that result in slightly less
severe phenotypes. These include OCA1B (affected individuals are
born with white skin and hair but develop some pigment with age
and express less severe ocular findings than in OCA1A), OCA1TS
(tyrosinase is temperature-sensitive and active in cooler regions of
the body resulting in a phenotype similar to that of the Siamese cat)
and platinum OCA (small amounts of pigment accumulate in the hair
and eyes in late childhood resulting in a silver tinge).[22] A recent study
identified a potential therapeutic for OCA1 where some tyrosinase
activity is present. Onojafe et al.,[23] having noted that nitisinone
(used in the treatment of hereditary tyrosinemia type 1) caused an
increase in serum tyrosine levels, treated OCA1B mice with the drug
and noted an improvement in pigmentation of the mice.[23] This is the

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first potential therapeutic treatment of OCA and may even be of use
in prenatal treatment to prevent the optic tract misrouting that results
in loss of visual acuity. The effects of nitisinone on a developing fetus
are not known; however, at least one patient has been reported to
have had a successful pregnancy while taking nitisinone,[24] although
no clinical studies have been performed to date.
OCA2
OCA2 is the most common form of albinism worldwide due to
its high prevalence in southern Africa, where it occurs in 1/3 900
blacks.
[21] Affected individuals are born with some pigmentation and
there is a slight increase in pigmentation with age. Hair colour ranges
from yellow to light brown, while the skin is white. In some families,
affected individuals develop multiple freckles in sun-exposed areas.
Ocular findings are generally less severe than those in OCA1A.
OCA2 results from mutations in the human homologue of the
mouse pink-eyed dilution gene, OCA2 (formally known as the
Pgene). The OCA2 gene is predicted to encode a transport or channel
protein,[25] although its precise function is not known. OCA2 was
mapped to human chromosome 15q11-12 and showed evidence
of locus homogeneity in black South African (SA) families with
OCA2.
[26] OCA2-associated haplotypes suggested multiple mutations
and mutation analysis revealed one common mutation, a 2.7 kb
deletion of exon 7, among these families.[20]
The origin of the deletion has been traced back to a founding
mutation in central Africa.[20] In parts of Africa, including SA,
about 80% of OCA2 chromosomes will carry the deletion, making
it a useful diagnostic tool. A subsequent study investigating non-
2.7kb alleles in affected individuals from different regions in Africa
(including SA, Lesotho, Zimbabwe and the Central African Republic)
found no second common mutation.[27]
OCA2B, known as brown albinism (Fig. 1), is much milder
than OCA1 and OCA2. It was first described in Nigeria,[28] but we
have since shown that it is a milder form of OCA2 resulting from
mutations in the OCA2 gene.[29] Individuals with brown albinism
have a cream to tan skin, beige to light brown hair and blue-green to
brown irides. Freckles, similar to those seen in OCA2, may develop
in sun-exposed areas.
OCA3
OCA3 (also known as rufous OCA) results from autosomal recessive
mutations at the TYRP1 locus, at least in patients of African
descent. Like OCA2, the precise function of this gene is not known,
however, pigment production is significantly reduced in its absence.
The prevalence of OCA3 among southern African blacks is at
least 1/8580, with a carrier rate of approximately 1/46,[30] while it
is extremely rare in the remainder of the world. Witkop et al.[31]
first described the characteristics of rufous albinism as ‘mahogany
red to deep red’ hair, reddish-brown skin, occasional presence of
pigmented nevi or freckles, reddish-brown to brown eye colour, slight
transillumination of the iris, fundal pigment, nystagmus, photophobia
and approximately 20/100 visual acuity (Fig. 2). Susceptibility to
solar damage and skin neoplasia is lower than for OCA2 and brown
OCA individuals. Affected individuals showed no evidence of
photoaging, photodamage or carcinomas.[30] Our research identified
two mutations that result in premature stop codons[29] and account
for 90% of the mutated TYRP1 alleles in southern African individuals
with OCA3. Both are nonsense mutations and there is unlikely to be
any residual enzyme activity. Unlike normal black skin where the
melanocytes contain mostly mature eumelanosomes, melanocytes in
OCA3 skin contain both eumelanosomes and phaeomelanosomes at
various stages of melanisation. Many of the organelles are, however,
aberrant, ‘crescent’- or racquet-shaped and have melanin only at the
edges.[32]
Studies in mouse models have shown that TYRP1, also contributes
to tyrosinase maturation. In melanocytes lacking TYRP1, tyrosinase
accumulates in the ER,[33] though to a lesser degree than in OCA2-null
melanocytes. TYRP1 has also been shown to stabilise tyrosinase,[34]
leading to the suggestion that TYRP1 is required for transfer of
tyrosinase from the ER to the Golgi.[35]
Genetic testing for OCA
Identification of the genes involved in these pigmentation disorders
has facilitated the development of prenatal testing. Several groups
have demonstrated the utility of genetic testing for albinism and
five prenatal diagnoses have been carried out in the Human
Genetics laboratory at the National Health Laboratory Service and
University of the Witwatersrand, Johannesburg (F Essop, personal
communication). Given that one mutation accounts for the majority
of albinism in southern Africa, prenatal diagnosis may be a feasible
option until effective therapies become available.
Vitiligo
Another type of pigmentation disorder common in southern Africa
is vitiligo. Vitiligo affects 1 - 2% of people worldwide, occurring
Fig. 1. Woman with brown oculocutaneous albinism.
Fig. 2. Hands of an individual with rufous oculocutaneous albinism.

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with similar frequencies in all ethnic groups. Phenotypically, it is
characterised by acquired depigmented patches of skin resulting from
the death of melanocytes. Various forms, defined by the distribution
of the depigmented lesions, have been identified. These include
generalised vitiligo (vitiligo vulgaris), the most common form with
widely distributed, symmetric and progressive lesions; and segmental
vitiligo, which presents with unilateral depigmented patches. The
focus of this part of the review will be generalised vitiligo (referred to
hereinafter as vitiligo).
Similar to OCA, vitiligo has a major impact on the physical and
mental health of patients. Melanocyte loss reduces melanin-derived
photoprotection of the skin and can compromise cutaneous immunity.
Ocular melanocytes are occasionally lost, causing photophobia
and night blindness.[36] Depigmentation commonly affects visible
areas such as the face and hands, which has a significant impact on
psychological well-being, especially among people of colour. Studies
have shown that individuals with vitiligo are embarrassed by their
appearance and usually feel uncomfortable socialising, leading to
severe depression in some cases and, on rare occasions, suicide.[3] The
early age of onset, typically in the first two decades of life, exacerbates
the negative impacts of this disorder, preventing individuals from
finding employment and even partners.[37]
The pathophysiology of vitiligo is not well understood and there
are few predictors of disease progression. While some individuals
experience extensive pigment loss that may eventually affect the
entire body, others undergo periodic changes in lesion size and
number. Spontaneous repigmentation due to melanocyte migration
from perilesional skin or unaffected hair follicles into areas of
loss has been observed (Fig. 3). Treatments range from the use of
topical corticosteroids and calcineurin inhibitors to UV combination
treatments and, in some cases, skin grafting. In addition to potential
side-effects such as skin atrophy, hyperpigmentation and scarring,
these therapies are not effective in all patients and may have limited
long-term results. The lack of new therapies is primarily due to the
lack of clarity with regard to the aetiology of vitiligo.
Aetiology
Vitiligo is a multifactorial, non-Mendelian disorder which is associated
with multiple loci. Vitiligo is thought to occur when melanocytes are
unable to combat the stress induced by an environmental trigger
such as severe sunburn, stress, vaccination, radiotherapy or exposure
to cytotoxins.[38] In individuals genetically susceptible to developing
vitiligo, the trigger event results in melanocyte dysfunction or death
that, in turn, initiates an immune response which causes the spread
of melanocyte loss. While vitiligo does not result in inflammation on
the scale of skin disorders such as psoriasis, ‘microinflammation’ may
also contribute to the onset of autoimmunity.[39]
A genetic component to vitiligo has long been suspected, due to
the fact that incidence is higher among family members of affected
individuals than in the general population. Recent genome-wide
association studies have begun to identify the genetic factors that
determine susceptibility to vitiligo.[40]
While the factors that initiate the onset of vitiligo are unclear
at present, autoimmunity appears to be the mechanism by which
lesions spread to multiple locations. The presence of antibodies
targeting melanocyte-specific proteins in sera from patients has
been reported on multiple occasions. Furthermore, 20 - 25% of
patients with vitiligo have another autoimmune disorder such
as psoriasis, diabetes and rheumatoid arthritis.[41] A number of
immune-related genes have been found to associate with increased
risk of vitiligo, including major histocompatibility class (MHC) I
molecules as well as genes involved in autoimmune disorders, such
as diabetes (UBASH3A and PTPN22) and rheumatoid arthritis
(C1QTNF6).[40] In addition, melanocyte-specific genes have also
been associated with increased risk, including OCA2, MC1R and
TYR, which are thought to be the source of melanocyte-specific
antigens.[42]
Oxidative stress and vitiligo
A constant factor in many hypotheses regarding the pathobiology of
vitiligo is the involvement of oxidative stress. Studies have suggested
that individuals with vitiligo have a compromised antioxidant
response,[43] with enzymes such as catalase and superoxide dismutase
present at higher than expected levels in tissue from perilesional areas
and in sera from patients with vitiligo. [44]
Melanocytes in perilesional sites of vitiligo patients display
hallmark dilation of the ER.[45] The ER is a sensor of cellular stress.
Furthermore, protein maturation, which occurs primarily in the ER,
requires a tightly regulated environment that allows for chemical
bond formation which determines secondary and tertiary protein
structure. Thus, disruption of the ER redox balance following cellular
oxidative stress results in misfolded proteins, which in turn activates
a stress pathway known as the unfolded protein response (UPR).
The UPR ameliorates stress caused by accumulation of misfolded
proteins in the ER by signalling a transient halt in global protein
synthesis, increasing expression of chaperones that facilitate protein
folding and increasing degradation of misfolded proteins.[46] The
Manga laboratory has shown that chemical agents that trigger vitiligo
induce oxidative stress that activates the UPR, suggesting a role for
this pathway in the pathogenesis of vitiligo.[47] Interestingly, the UPR
is activated in other autoimmune disorders such as type I diabetes[48]
and contributes to activation of the immune response.
UPR activation in melanocytes results in increased expression of
cytokines, such as interleukin (IL)-6 and -8 that can attract immune
components to the skin which initiate an autoimmune response.
[47] These cytokines have been found previously to be expressed at
higher levels in perilesional compared with normal skin in vitiligo
patients, suggesting that they may indeed play a role in the aetiology
of vitiligo. This study thus identified a key link between events that
trigger vitiligo and the onset of autoimmune disease.
Conclusion
Decades of work on albinism in SA, influenced by the views and
contributions of Trefor Jenkins, his students and co-workers, has
contributed to understanding the social and cultural milieu of
Fig. 3. Vitiligo lesion displaying repigmentation. (Photo courtesy of SJ Orlow,
New York University School of Medicine.)

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albinism, the medical risks and implications, and unravelling the
molecular basis and aetiology for OCA2 on the sub-continent
(Table 1). The demystification of albinism and work with the
Albinism Society of South Africa (http://www.albinism.org.za/),
under the direction of Nomisonto Masibuko, has contributed to
acceptance of the condition and empowerment to deal with this
manageable trait to minimise the adverse effects on the lives of those
with albinism.
As our understanding of the molecular basis of pigmentation
improves, effective and long-lasting therapies are likely to become
a reality for individuals with pigmentary disorders. Demonstrating
that tyrosinase maturation and trafficking is key to multiple forms
of OCA may make it feasible to develop a single approach for
the treatment of multiple forms of OCA, while the identification
of cytokines involved in the onset of vitiligo may facilitate the
development of targeted therapies. Chaperones that promote protein
folding are currently being developed for the treatment of Fabry’s
disease (Amicus Therapeutics), which results from misfolding of the
enzyme α-galactosidase A, and antibodies targeting IL-6 are being
tested for use in the treatment of non-small cell lung cancer.[49] Thus,
therapies for OCA and vitiligo may now become a reality.
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Accepted 25 July 2013.