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


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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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984 December 2013, Vol. 103, No. 12 (Suppl 1) SAMJ
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
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 (
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 1/3900 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.
985 December 2013, Vol. 103, No. 12 (Suppl 1) SAMJ
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 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
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 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
986 December 2013, Vol. 103, No. 12 (Suppl 1) SAMJ
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 is the most common form of albinism worldwide due to
its high prevalence in southern Africa, where it occurs in 1/3 900
[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
[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 (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 1/8580, 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
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.
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.
987 December 2013, Vol. 103, No. 12 (Suppl 1) SAMJ
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.
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
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.
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.)
988 December 2013, Vol. 103, No. 12 (Suppl 1) SAMJ
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 (,
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.
... Convincing evidence for differences in risk among various types of albinism is lacking at present, but there may be differences related to different gene mutations. Mutations in genes encoding for tyrosinase (OCA 1A and OCA 1B), P-protein (OCA 2), tyrosinase-related protein (OCA 3), and MATP (OCA 4) have been identified [10][11][12][13]. OCA 5 phenotype has been recently reported among the members of a consanguineous Pakistani family, linked to an as yet unidentified specific gene mapped to the 4q24 chromosome region [14]. ...
... OCA 5 phenotype has been recently reported among the members of a consanguineous Pakistani family, linked to an as yet unidentified specific gene mapped to the 4q24 chromosome region [14]. Gene mutation analysis was not performed in the index patient due to limited access to fresh frozen samples and financial constraints, but her phenotype fitted into the classic OCA 2 subtype (straw-colored hair, eyebrows, eyelashes, blue/gray eyes) which is by far the most prevalent type of OCA among South African blacks, affecting 1 in 3,900 individuals [11,13]. Consanguinity plays an important role in various ethnic groups in the African population [11], but this was not the case in our patient. ...
... Interestingly, in MCPyV-negative tumors, several of these pathways are altered by genetic mutations, e.g., in TP53, RB1, NOTCH1-4, FAT-1, PRUNE-2, linked to UV signature events [13,17,18]. The presented patient fits within the latter scenario as we could not detect MCPyV [19,20]. ...
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Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm of presumed neuroendocrine origin, with aggressive behavior and poor prognosis, that tends to have an increased incidence among elderly Caucasians and immunosuppressed individuals. MCC is either associated with a clonal integration of the Merkel cell polyoma virus into the host genome or with genomic alterations caused by chronic UV exposure. Tumors of either carcinogenesis show epithelial, neuroendocrine, and B-lymphoid lineage markers. HIV-infected African albinos have a higher risk of developing skin cancers, including MCC, in comparison with the general population. We report a case of MCC of the head in a young albino woman with a HIV/HTLV-1 coinfection. The patient also suffered from multiple squamous cell carcinomas of the scalp, face, lip, and ears, suggesting an UV carcinogenesis of MCC. The purpose of this case report is to emphasize the relationship between immunosuppression (HIV/HTLV-1 coinfection, chronic sun exposure, ocular-cutaneous albinism, pregnancy) and MCC. It highlights the importance of early diagnosis, dermatological screening with a risk-stratified surveillance, particularly in immunosuppressed albino patients in sub-Saharan Africa, and multidisciplinary management of this biologically unique cutaneous cancer.
... OCA2 is the commonest globally with a prevalence of almost 1 in 3900 in southern parts of Africa, 1 in 10,000 in African Americans and 1 in 30,000 in Caucasians. [5][6][7][8] Mutations in tyrosinase-related protein 1 (TYRP1) result in OCA3 ("Rufous oculocutaneous albinism"). TYRP1 spans 17KB genomic DNA and catalyzes the oxidation of DHICA (5,6-dihydroxyindole-2-carboxylic acid) monomers to melanin. ...
... [9][10][11][12][13] OCA3 occurs in about 1 in 8500 patients of African ethnicity and is associated with a relatively mild OCA phenotype. 5,14 OCA4 (OMIM #606574) is caused by mutations in SLC45A2, which spans 40kb of genomic DNA and encodes a membrane-associated transporter protein (MATP). This subtype is largely confined to Japanese patients, accounting for approximately 25-27% of cases. ...
Albinism describes a heterogeneous group of genetically determined disorders characterized by disrupted synthesis of melanin and a range of developmental ocular abnormalities. The main ocular features common to both oculocutaneous albinism (OCA), and ocular albinism (OA) include reduced visual acuity, refractive errors, foveal hypoplasia, congenital nystagmus, iris and fundus hypopigmentation and visual pathway misrouting, but clinical signs vary and there is phenotypic overlap with other pathologies. This study reviews the prevalence, genetics and ocular manifestations of OCA and OA, including abnormal development of the optic chiasm. The role of visual electrophysiology in the detection of chiasmal dysfunction and visual pathway misrouting is emphasized, highlighting how age-associated changes in visual evoked potential (VEP) test results must be considered to enable accurate diagnosis, and illustrated further by the inclusion of novel VEP data in genetically confirmed cases. Differential diagnosis is considered in the context of suspected retinal and other disorders, including rare syndromes that may masquerade as albinism.
... 52 After differentiation of melanocytes, MITF regulates the expression of genes during exposure to ultraviolet radiation (UVR), promoting tanning of the skin. 53 Melanin is a polymer pigment produced in melanocytes. Its synthesis occurs through enzyme reactions, which convert tyrosine into melanin through the tyrosinase enzyme. ...
... 57 OCA2 is the most prevalent form of albinism in Africa. 5,35,53 The disorder affects those of African descent more often than Caucasians and is characterized by mutation in the OCA2 gene (previously known as the P gene), which encodes the P protein. 5,57 Its exact functions are not fully understood, but the P protein appears to be involved with the transport of proteins to melanosomes, stabilizing the melanosomal protein complex and the regulation of the pH of the melanosome and/or metabolism of glutathione, all of which are key for melanin production. ...
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Oculocutaneous albinism is an autosomal recessive disease caused by the complete absence or decrease of melanin biosynthesis in melanocytes. Due to the reduction or absence of melanin, albinos are highly susceptible to the harmful effects of ultraviolet radiation and are at increased risk of actinic damage and skin cancer. In Brazil, as in other parts of the world, albinism remains a little known disorder, both in relation to epidemiological data and to phenotypic and genotypic variation. In several regions of the country, individuals with albinism have no access to resources or specialized medical care, and are often neglected and deprived of social inclusion. Brazil is a tropical country, with a high incidence of solar radiation during the year nationwide. Consequently, actinic damage and skin cancer occur early and have a high incidence in this population, often leading to premature death. Skin monitoring of these patients and immediate therapeutic interventions have a positive impact in reducing the morbidity and mortality associated with this condition. Health education is important to inform albinos and their families, the general population, educators, medical professionals, and public agencies about the particularities of this genetic condition. The aim of this article is to present a review of the epidemiological, clinical, genetic, and psychosocial characteristics of albinism, with a focus in skin changes caused by this rare pigmentation disorder.
... In Oculocutaneous albinism, the hair, skin and eyes are affected while in Ocular albinism the features is confined to the eyes and visual system [2]. The most common variants of albinism and their responsible genes are: Ocular albinism (OA1gene), OCA1 (Tyrosine TYR gene), OCA2/Brown OCA (P gene)-which is the commonest in Africa, OCA3/Rufous OCA (Tyrosine-related protein-1, TRP-1 gene) and OCA4 (SLC45A2 gene) [3][4][5]. ...
... [39] In one form, as a result of a founder mutation in Africans, a mutation in the oculocutaneous albinism 2 (OCA2) gene leads to an incidence of 1/3 900 SA individuals. It is therefore the most common recessive disorder in SA, with 80% of patients carrying a 2.7 kb deletion in exon 7. [40] The deletion leads to reduced production of a protein essential to melanin production. Given the complexity of skin structure, an ex vivo therapeutic approach involving gene correction, and subsequent transplantation of healthy melanocytes, is not currently feasible. ...
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South Africa encompasses extraordinary genetic diversity, frequently revealing unique mutations and variations associated with disease. Despite the advances of traditional gene therapy, our understanding of causative mutations in the South African population has, for the most part, contributed to diagnostic rather than therapeutic interventions. Recent developments in genome engineering and its ease of use have released a powerful tool with which to intervene in otherwise untreatable disease. In addition, harnessing this tool for discrete genetic edits provides a mechanism by which screening of new drugs specific to our population's diversity can be accomplished. Here, we use examples of some of the most advanced genome engineering approaches to develop therapeutic strategies that would specifically affect South African individuals.
... to the formation of slight yellow hair in the first few years and gradual accumulation over time in patients with OCA1B [6] . OCA3 was found in Africa, and it was rarely seen in other populations [7] . OCA4 was mainly observed in Japanese population [8] . ...
Oculocutaneous albinism (OCA) is an autosomal recessive pigmentation abnormality, characterized by variable hair, skin, and ocular hypopigmentation. OCA1 is the most frequent subtype of OCA, caused by mutations in the tyrosinase gene (TYR). In this study, we investigated the genetic mutation of a Chinese family with a female OCA patient who came for genetic counseling before pregnancy. Complete physical examination was performed, and DNA from blood samples was collected from the family members. Mutations of TYR, OCA2, and SLC45A2 genes were examined in the proband, and verified in her parents by Sanger sequencing. Large deletion or duplication of TYR and OCA2 genes was detected by multiplex ligation-dependent probe amplification (MLPA). A homozygous TYR c.307T>C (p.Cys103Arg) missense mutation was identified in the proband, and both parents were heterozygous carriers. No large deletion or duplication was found in the proband. This mutation was absent in 1000G, ExAC, or HGMD database, and multiple lines of in silico tools supported a deleterious effect. These results suggest that TYR c.307T>C mutation might be responsible for OCA1, and our study further expands the mutation spectrum of OCA1 in the Chinese population.
... The lack of melanin results in a pale skin and increased risk of skin cancer (see Chap. 41). The eyes should be protected in all types of albinism by dark UV-blocking sunglasses [23]. OCA is further divided into several subtypes depending on the particular genetic mutation, with or without associated syndromes: ...
Although most dermatoses inducing changes of the content and distribution of melanin discoloring the skin are not life-threatening, they have a tremendous psychological and socioeconomic impact among people with skin of color, particularly in African populations with darkly pigmented or black skin. There is a plethora of genetic and/or acquired diseases associated with various types of leukoderma; postinflammatory hypo- and hyperpigmentations are most common in African populations as secondary response after various dermatoses, burns, injuries, surgical interventions, injections, and action of chemicals [1]. They are all disfiguring and cause major psychological discomfort to the patients, with vitiligo being the most prevalent cause of deep concern [2].
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Albinism encompasses a group of hereditary disorders characterized by reduced or absent ocular pigment and variable skin and/or hair involvement, with syndromic forms such as Hermansky–Pudlak syndrome and Chédiak–Higashi syndrome. Autosomal recessive oculocutaneous albinism (OCA) is phenotypically and genetically heterogenous (associated with seven genes). X-linked ocular albinism (OA) is associated with only one gene, GPR143. We report the clinical and genetic outcomes of 44 patients, from 40 unrelated families of diverse ethnicities, with query albinism presenting to the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between November 2017 and October 2019. Thirty-six were children (≤ 16 years) with a median age of 31 months (range 2–186), and eight adults with a median age of 33 years (range 17–39); 52.3% (n = 23) were male. Genetic testing using whole genome sequencing (WGS, n = 9) or a targeted gene panel (n = 31) gave an overall diagnostic rate of 42.5% (44.4% (4/9) with WGS and 41.9% (13/31) with panel testing). Seventeen families had confirmed mutations in TYR (n = 9), OCA2, (n = 4), HPS1 (n = 1), HPS3 (n = 1), HPS6 (n = 1), and GPR143 (n = 1). Molecular diagnosis of albinism remains challenging due to factors such as missing heritability. Differential diagnoses must include SLC38A8-associated foveal hypoplasia and syndromic forms of albinism.
The deep evolutionary history of African populations, since the emergence of modern humans more than 300,000 years ago, has resulted in high genetic diversity and considerable population structure. Selected genetic variants have increased in frequency due to environmental adaptation, but recent exposures to novel pathogens and changes in lifestyle render some of them with properties leading to present health liabilities. The unique discoverability potential from African genomic studies promises invaluable contributions to understanding the genomic and molecular basis of health and disease. Globally, African populations are understudied, and precision medicine approaches are largely based on data from European and Asian-ancestry populations, which limits the transferability of findings to the continent of Africa. Africa needs innovative precision medicine solutions based on African data that use knowledge and implementation strategies aligned to its climatic, cultural, economic and genomic diversity. Africa is a continent with deep evolutionary history, which has implications for the genetic underpinnings of disease. In this Review, the authors discuss how genetic features of African populations provide both challenges and opportunities for understanding disease genetics in Africa. They describe how this genetic knowledge — combined with initiatives including capacity-building, data sharing and increased representation of African genomes in genetic variation databases — can be leveraged towards achieving precision medicine approaches in African healthcare.
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Vitiligo is characterized by depigmented skin patches caused by loss of epidermal melanocytes. Oxidative stress may have a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study, we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol and monobenzyl ether of hydroquinone, known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box-binding protein 1 (XBP1), is increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators IL6 and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while overexpression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.
A 19 year old woman with tyrosinaemia type 1 gave birth to a healthy girl after 41 weeks of gestation. Nitisinone was continued throughout the pregnancy (maternal levels 68–96 μmol/l, target level 30–60 μmol/l). Tyrosine levels during pregnancy were between 500 and 693 μmol/l (normal values 20–120 μmol/l) and phenylalanine levels between 8 and 39 μmol/l (normal values 30–100 μmol/l). Nitisinone was measurable in neonatal blood immediately after birth, at a level comparable to the simultaneous level in the mother. Nitisinone half-life in the neonate was estimated to be 90 h. Tyrosine levels in the neonate decreased from 1,157 μmol/l at birth (cord blood) to normal levels within 4 weeks. Phenylalanine levels in the neonate were normal from birth on. The child had a normal psychomotor development as assessed throughout the first year of life. This is the first report worldwide of a pregnancy during treatment with nitisinone. In this case, no adverse effects of nitisinone, maternal high tyrosine or low phenylalanine were detected in the child, so far. Long-term results in a larger cohort of pregnancies and births are needed to determine whether nitisinone can be administered safely during pregnancy.
The albino (tyrosinase, Tyrc), brown (tyrosinase-related protein 1, Tyrp1b) and slaty (tyrosinase-related protein 2, tyrp2slt) loci are all involved in the regulation of melanogenesis. Phenotypes of inbred mice mutant at two or more of these loci are not always explicable by simple summation of the established or suspected catalytic functions of the gene products. These phenotypes suggest that relationships among the proteins extend beyond the obvious fact that they catalyze different steps in the same melanogenic pathway, and that they may also interact intimately in such a way that a mutation in one impacts the function of the other(s). Previous studies have attributed catalytic activities to each member of this trio; however, it has been difficult to study the proteins individually, either in vivo or in tissues or cells. Therefore, we undertook to transfect the genes, in revealing combinations, into COS-7 cells (which have no melanogenic apparatus of their own) to clarify the interacting functions of their encoded proteins. Specifically, we attempted to evaluate the effects of Tyrp1 and Tyrp2 proteins on tyrosinase protein. We report evidence that Tyrp1 stabilizes tyrosinase, confirming previous observations, and, in addition, demonstrate that Tyrp1 decreases tyrosinase activity. By contrast, Tyrp2 increases tyrosinase activity by stabilizing the protein. We conclude that both Tyrp1 and Tyrp2, in addition to other catalytic functions they may possess, act together to modulate tyrosinase activity.
Background One determining factor of skin colour is the distribution pattern of melanosomes within keratinocytes. Melanosomes in keratinocytes of light skin as in Caucasians are distributed as membrane-bound clusters, whereas the melanosomes in keratinocytes of dark skin as in African/American individuals tend to be larger and distributed individually. It has been shown that melanin content, melanin composition and the size of melanosomes in the human epidermis vary considerably with both ethnicity and chronic sun exposure. Objectives To assess quantitatively the distribution pattern of melanosomes that have been transferred to keratinocytes in the photoprotected (volar forearm) skin from normal Asian individuals and to compare these data with those from light-skinned Caucasian and dark-skinned African/American individuals. Methods Electron microscopy was used. Results We have demonstrated that melanosomes within keratinocytes of Asian skin are distributed as a combination of individual and clustered melanosomes with a proportion of 62·6% vs. 37·4%, respectively. This contrasts with dark and light skin keratinocytes where melanosomes are predominantly individual (88·9%) and clustered (84·5%), respectively. Analysis of mean ± SD melanosome size also revealed a progressive variation in size with ethnicity, melanosomes in dark skin being the largest (1·44 ± 0·67 μm2 × 10−2) followed in turn by those in Asian skin (1·36 ± 0·15 μm2 × 10−2) and Caucasian skin (0·94 ± 0·48 μm2 × 10−2). In addition, it was shown that the melanosomes that are individually distributed tend to have a larger size than the clustered melanosomes. Conclusions The present data indicate that there may be a size gradient of melanosomes encompassing the global complexion coloration and that the melanosome distribution in keratinocytes of Asian skin is intermediate between that in light Caucasian and dark African/American skin.
Oculocutaneous albinism (OCA) is an inherited disorder resulting in hypopigmentation of the skin, hair, and eyes. OCA type 2 (tyrosinase-positive) is the most common recessively inherited disorder among southern African Blacks. OCA2 is also seen in southern African Caucasoids, but is less frequent. The gene responsible for this type of albinism, P, is the human homolog of the mouse pink-eyed dilution gene. Mutations at this locus are also responsible for the milder hypopigmentation phenotype seen in individuals with brown oculocutaneous albinism (BOCA). A common African P mutation was identified in Black OCA2 individuals, and has since been shown to occur in Black individuals with brown OCA as well. This mutation is a 2.7 kb interstitial deletion. In this study, we undertook to screen the coding region of the P gene for mutations in the non-2.7 kb deletion alleles of OCA2 patients who did not carry the deletion allele in either one or both of their P genes. We identified four mutations (A334V, 614delA, 683insT, 727insG) in a group of 39 unrelated Black OCA2 patients with a total of 52 non-2.7 kb deletion OCA2 genes. When taking all OCA2 cases into consideration, including those homozygous for the 2.7 kb deletion mutation, these account for a further 1.7% of OCA2 mutations in southern African Blacks, increasing the overall mutation detection rate to 78.7%. Three mutations (E678K, L688F, I370T) were identified in a group of 15 Black patients with an initially unclassified type of OCA and another three mutations (IVS 14-2 (a→g), V350M, P743L) were identified in nine Caucasoid OCA patients. Relatively few mutations, all with low frequency, were identified in the non-2.7 kb deletion OCA genes. We propose that other mutations may lie either within intronic sequence or within the promoter region of the gene. Hum Mutat 15:166–172, 2000. © 2000 Wiley-Liss, Inc.
Type I (tyrosinase related) oculocutaneous albinism (OCA) results from mutations of the tyrosinase gene on chromosome 11q that lead to reduced or absent melanin pigment synthesis. The phenotype of Type I OCA is broad, ranging from a total lack to only a moderate reduction of melanin, and the phenotypic variation is associated with different mutant alleles at the tyrosinase locus. A total of 36 mutations have been identified in Type I OCA including 24 missense, 4 nonsense, and 8 frameshift mutations. The majority of affected individuals have been compound heterozygotes with different maternal and paternal alleles. Six polymorphic sites for haplotype analysis have been identified in the tyrosinase gene including 2 in the promoter region, 2 in the coding region associated with alternative amino acids in the protein, and 2 RFLPs in the first intron. © 1993 Wiley-Liss, Inc.
We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10(-8)), MC1R (P = 1.82 × 10(-13)), a region near TYR (P = 1.57 × 10(-13)), IFIH1 (P = 4.91 × 10(-15)), CD80 (P = 3.78 × 10(-10)), CLNK (P = 1.56 × 10(-8)), BACH2 (P = 2.53 × 10(-8)), SLA (P = 1.58 × 10(-8)), CASP7 (P = 3.56 × 10(-8)), CD44 (P = 1.78 × 10(-9)), IKZF4 (P = 2.75 × 10(-14)), SH2B3 (P = 3.54 × 10(-18)) and TOB2 (P = 6.81 × 10(-10)). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration.