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Keywords:

  • biology;
  • genes;
  • hereditary skin diseases;
  • hypomelanoses;
  • melanin;
  • melanocyte;
  • molecular defects

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Brief description of the biology of melanocytes
  5. Genetic skin hypomelanoses
  6. Disorders of melanin synthesis
  7. Disorders of melanosome formation and transfer to keratinocytes
  8. Conclusions
  9. Funding sources
  10. Conflict of interest disclosure
  11. References

Abstract:  Inherited diseases of pigmentation were among the first traits studied in humans because of their easy recognition. The discovery of genes that regulate melanocytic development and function and the identification of disease-causative mutations have greatly improved our understanding of the molecular basis of pigmentary genodermatoses and their underlying pathogenetic mechanisms. Pigmentation mutants can account for hypo-/amelanosis, with or without altered melanocyte number, resulting in different phenotypes, such as Waardenburg syndrome, piebaldism, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, oculocutaneous albinism and Griscelli syndrome. In this review, we summarize the basic concepts of melanocyte biology and discuss how molecular defects in melanocyte development and function can result in the development of hypopigmentary hereditary skin diseases.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Brief description of the biology of melanocytes
  5. Genetic skin hypomelanoses
  6. Disorders of melanin synthesis
  7. Disorders of melanosome formation and transfer to keratinocytes
  8. Conclusions
  9. Funding sources
  10. Conflict of interest disclosure
  11. References

Cutaneous pigmentation is an extremely complex human trait, ranging from white or pink to tan, dark brown or black and displaying a marked variation even within a particular ethnic group. Skin colouration is influenced by a variety of factors, such as melanin, capillary blood flow, cutaneous chromophores (lycopene, carotene) and collagen in the dermis. Other important factors such as physical factors may also contribute to the observed skin colour, including the spectrum of light striking the skin, the reflection, refraction and absorption of light and the transparency of the stratum corneum and epidermis. For the most part, however, the colour of the skin is controlled by the pigmentary system, i.e. melanocytes and melanin, and is primarily determined by the quantity, type and distribution of melanin within the skin. The synthesis of melanin is a complex multistep process, catalysed by at least one or several enzymes, the most prominent of which is tyrosinase. The type of melanin as well as its distribution within melanosomes is not a random event but is genetically regulated by a number of genes such as MC1R, TYR, OCA2, SLC24A5, MATP and ASIP.

Abnormal changes of skin colour are observed in a vast number of diverse disorders with different underlying mechanisms. Essentially, any change of the components that contribute to normal skin colour, resulting in their excess or deficiency within the skin will produce an altered cutaneous colouration. Various classification schemes have been employed but the terminology used by clinicians to describe coloured changes remains confusing. Most use the term ‘pigmentation’ disorders as synonymous to ‘melanotic’ disorders to include entities that are characterized by a pathological change in melanin or melanocytes and differentiate these from the ‘non-melanotic’ disorders which are due to alterations of other cutaneous chromophores. Melanotic disorders are broadly divided into hypermelanotic (due to excess melanin but normal melanocytic population) and hypermelanocytic (due to normal melanin and increased melanocytic proliferation) as well as hypomelanotic/amelanotic and hypomelanocytic/amelanocytic which are due to melanin deficiency and reduction or absence of melanocyte number respectively. Further categorization distinguishes these groups into congenital and acquired, circumscribed, mixed and generalized, epidermal, dermal and mixed groups (1,2).

Over the past few decades, significant advances based on the study of murine coat colour mutants have contributed to our understanding of the physiology and pathophysiology of the pigmentation process. Molecular defects and genetic mutations in critical components of the pigmentary system, have been identified and have helped explain the phenotypic features manifesting in several genetic disorders of pigmentation (3). (Tables 1–4) Mutations affecting pigmentation disregulate melanocytes at specific points of their development and function, such as (4):

Table 1.   Pigmentary disorders of melanoblast migration from the neural crest
Genodermatosis (MIM#)Inheritance, GeneDermatological characteristicsAssociated findings
  1. WS, Waardenburg syndrome; AD, autosomal dominant; AR, autosomal recessive; SCF, stem cell growth factor; EDN3, endothelin 3; MITF, microphthalmia transcription factor.

WS1 (193500)AD PAX3Congenital piebald-like white patches in skin and hair more frequentHeterochromia irides, dystopia canthorum, congenital deafness
WS2 (193510) (608890) (611584) (606662)AD, AR MITF SLUG SOX10Congenital piebald-like white patches in skin and hairNo dystopia canthorum heterochromia irides more frequent, deafness
WS3 (148820) AD, AR PAX3WS1 featuresWS1 features, limb anomalies
WS4 (277580)AD SOX10 EDN3 EDNRBCongenital piebald-like white patches in skin and hairHirschsprung disease
Tietz syndrome (103500)AD MITFHypopigmentationDeafness
Piebaldism (172800)AD c-Kit SCF SLUGWhite forelock White, depigmented areas of skinNone
Table 2.   Pigmentary disorders of melanin synthesis: oculocutaneous albinism Thumbnail image of
Table 3.   Pigmentary disorders of melanin/melanosome synthesis Thumbnail image of
Table 4.   Disorders of mature melanosome transfer in the melanocyte Thumbnail image of
  • 1
    melanoblast migration from the neural crest to the skin [Waardenburg syndrome type 1–4 (WS1–4), piebaldism];
  • 2
    melanin synthesis in the melanosome [oculocutaneous albinism type 1–4 (OCA1–4)];
  • 3
    melanosome formation in the melanocytes [(Hermansky-Pudlak syndrome type 1–7 (HPS1–7), Chediak-Higashi syndrome (CHS1)];
  • 4
    mature melanosome transfer to the tips of the dendrites [Griscelli syndrome type 1–3 (GS1–3)].

In this article, we present a brief review of the different stages of melanocyte biology and discuss how the knowledge of the genes that control the pigmentary process has shed new light on the molecular pathogenesis and clinical expression of hereditary skin hypopigmentation.

Brief description of the biology of melanocytes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Brief description of the biology of melanocytes
  5. Genetic skin hypomelanoses
  6. Disorders of melanin synthesis
  7. Disorders of melanosome formation and transfer to keratinocytes
  8. Conclusions
  9. Funding sources
  10. Conflict of interest disclosure
  11. References

Melanocyte development and migration from the neural crest to homing sites

Melanocytes develop from melanoblasts, their neural-crest precursor cells. The neural crest cells arise from the most dorsal point of the neural tube (between the surface ectoderm and the neural plate) and represent a transient population of pluripotent cells that is only present during embryonic development. In addition to melanocytes, neural crest cells differentiate into peripheral and enteric neurons, adrenal chromaffin cells, chondrocytes and osteocytes in the cranial region, smooth muscle cells and other cell types (5). Melanoblasts, the precursors of melanocytes, migrate, proliferate and differentiate en route for their eventual destinations in the basal epithelium of the epidermis and hair bulbs of the skin, the uveal tract of the eye, the stria vascularis, the vestibular organ and the endolymphatic sac of the ear and the leptomeninges of the brain (3,6).

The development of the melanocyte lineage from the neural crest is regulated by various signalling pathways and transcription factors, functioning as a ‘logic circuit’ (Fig. 1). Key genes in this developmental pathway include PAX3 (paired-box 3), SOX10 [sex-determining region Y-box 10], MITF, KIT, endothelin 3 (EDN3) and endothelin receptor B (EDNRB) (7). The microphthalmia transcription factor (MITF) is the earliest melanocyte-specific transcription factor and functions as a key player in melanocyte development. It is a member of the Myc-related family of the basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors, and was originally described as a mouse coat colour mutant more than 60 years ago (8). Mutations of MITF lead to defects in melanocytes, the retinal pigmented epithelial cells of the retina, mast cells and osteoclasts (9). Consequently, homozygous mutant mice have small eyes (microphthalmia), white fur and deafness (8). Six mutations affecting the MITF have been identified in humans, occurring both in the protein/protein dimerization region and the DNA interactive region. Two of these are severe truncating mutations and two are nucleotide substitutions in the coding region for the helix-loop-helix-zipper dimerization motif.

image

Figure 1.  Biological function of melanocytes and genes that control the pigmentary pathway. MATP, membrane-associated transporter protein; MITF, microphthalmia transcription factor; TRP, tyrosinase-related protein; BLOC3, biogenesis of lysosome-related organelle complex; HPS, Hermansky-Pudlak syndrome; CHS, Chediak-Higashi syndrome; MYO5A, myosin 5A; MLPH, melanophilin; DCT, dopachrome tautomerase; EDN3, endothelin 3; EDNRB, endothelin receptor B.

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Following their migration to target sites, melanoblasts differentiate into the melanin producing cells – the melanocytes – synthesizing melanosomal granules within which the substrate tyrosine is converted to melanin polymers. By contrast, melanocytes in the non-cutaneous sites halt melanogenesis shortly after birth and retain their complement of melanosomes (6). MITF expression is required for the survival of migrating melanoblasts (8). Complete deficiency of MITF results in the absence of melanocytes, suggesting that MITF is essential for lineage survival and proliferation or to avert differentiation towards other neural-crest lineages (such as glia and neurons) (3). Transcriptional targets of MITF, such as bcl-2, cdk-2 and the cytokine receptor c-met, are also required by melanocytes to remain viable during their development and maintain their cell cycle.

Several cytokines and growth factors have been implicated in melanoblast transformation to functional melanocytes (10). It has been shown that the mast cell growth factor (c-Kit), a tyrosinase kinase receptor, is involved in melanoblast expansion, survival and migration. The interaction of Kit-ligand (KitL, also known as steel factor or stem cell growth factor, SCF) with the Kit receptor on the surface of the melanoblasts is necessary for the dispersal of melanocyte precursors from the migration staging area (5,11,12). c-Kit activation by KitL leads to Ras activation and multiple canonical signalling as well as post-translational modification of MITF (13). Mutations leading to reduction in receptors impair the survival and migration of the neural crest-derived melanoblasts, resulting in failure of their colonization at anatomical sites most distant to the neural crest (4).

Another gene required for melanoblast migration and/or survival is the SLUG gene (SNAIL), a zinc finger neural crest transcriptional factor (14). In mouse models of melanoma, the inhibition of SLUG by small RNA interference suppressed metastatic potential suggesting that SLUG may also be linked with metastasis-related behaviours (15). Additional mechanisms that seem to be involved in the late steps of melanocyte migration from the dermis into the epidermis, include endothelins 1 and 3, the cell adhesion molecule E-cadherin, hepatocyte growth factor and basic fibroblast growth factor (16). Furthermore, the melanocortins (adrenocorticotropic hormone, alpha-melanocyte stimulating hormone/α-MSH and β-endorphin) with their respective receptors have been implicated in melanocyte function (10).

Melanin synthesis

In their mature form, melanocytes synthesize and package melanin within discrete membrane-bound, lysosome-like organelles called melanosomes. Melanocytes are true secretory cells because the melanosomes are transferred or secreted via melanocytic dendrites to the surrounding keratinocytes of the epidermis and hair follicles (10). The term ‘epidermal melanin unit’ has been used to describe a single basal melanocyte surrounded by 36 keratinocytes to which it supplies melanin (17).

There are two types of melanin in human skin: the brown-black eumelanin and the yellow-red pheomelanin which differ not only in colour but also in the size, shape and packaging of their granules (18). Melanin biosynthesis is derived from tyrosine and is primarily regulated by tyrosinase, P gene, tyrosinase-related protein 1 (TRP1) and membrane-associated transporter protein (MATP). The obligatory step is the hydroxylation of tyrosine to dopaquinone from which 3,4-dihydroxyphenylalanine (l-DOPA) can also be derived (Fig. 2) (19). A ‘three enzyme theory’ is implicated with the initiation of melanogenesis. It was recently shown that l-tyrosine serves as a substrate for tyrosinase as well as for tyrosine hydroxylase isoform 1 (THI). l-tyrosine results from the conversion of l-phenylalanine by the enzyme phenylalanine hydroxylase (PAH). Of note, epidermal PAH activity is dependent on skin phototype, with darker skin demonstrating higher PAH activity, both constitutively as well as upon UVR exposure (20). The transcription and function of the three enzymes (tyrosinase, THI, PAH) are regulated by 3′,5′-cyclic adenosine monophosphate (cAMP)/cAMP response element. Therefore, cAMP is a key regulator of melanogenesis. Receptors that promote cAMP synthesis include MC1R, β-MSH/MC4R, the β2-adrenoceptor, the muscarinic receptors, the α- and β-oestrogen receptors and the Corticotropin releasing factor (CRF)/CRFR1 signal (20).

image

Figure 2.  The pathway of melanin synthesis.

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After dopaquinone synthesis, the eumelanin and pheomelanin pathways diverge. The eumelanogenesis pathway necessitates the presence of the tyrosinase-related proteins TRP1, (GP75 or b-locus) and TRP2 (dopachrome tautomerase, DCT). These two enzymes may serve as markers of differentiation. The pheomelanogenesis pathway involves conjugation of dopaquinone by thiol-containing cysteine or glutathione. Consequently, pheomelanin is more photolabile and may induce the production of oxidative superoxide and hydroxyl radicals, as well as hydrogen peroxide, which in turn, may cause further DNA damage.

The ratio of eumelanin to pheomelanin is regulated by a plethora of different factors, including pigment enzyme expression and the availability of tyrosine and sulphydryl-containing reducing agents in the cell (21). It is also controlled genetically by the melanocortin 1 receptor (MC1R) gene (chromosome 16q24.3), variations of which are responsible for physiological skin colour differences in healthy individuals (22,23). A clear dosage effect regarding MC1R variants has been shown, with heterozygotes tending to be intermediate between homozygotes and wild-type individuals for skin type, freckling and shade of hair (24). α-MSH, binds and activates MC1R, a G-coupled receptor, which through cAMP activation and a series of downstream events, leads to activation of MITF. In turn, MITF expression increases the transcription of pigment-synthesizing genes, such as tyrosinase and TRP1 and 2 (25). It was recently shown, however, that α-MSH and β-MSH can regulate tyrosinase activity directly in the melanosome in a receptor-independent way (26,27).

Melanosome formation and transfer to keratinocytes

As melanosomes accumulate pigment, they are transported down the melanocyte dendrites. Melanin is then packaged and delivered to keratinocytes by melanosomes (28,29). After entering keratinocytes, melanosomes are in response to Ultraviolet radiation (UVR), strategically put over the ‘sun-exposed’ side of nuclei to form cap-like structures resembling umbrellas (3).

Genetic skin hypomelanoses

  1. Top of page
  2. Abstract
  3. Introduction
  4. Brief description of the biology of melanocytes
  5. Genetic skin hypomelanoses
  6. Disorders of melanin synthesis
  7. Disorders of melanosome formation and transfer to keratinocytes
  8. Conclusions
  9. Funding sources
  10. Conflict of interest disclosure
  11. References

Human congenital disorders of pigmentation characterized by hypomelanosis, may originate from mutations affecting the complex pathway of melanocyte development and function. These mutations involve melanoblast development migration (piebaldism, WS and Tietz syndrome), melanin synthesis (oculocutaneous albinism), and melanosome formation and transfer to keratinocytes (HPS, CHS, GS).

Disorders of melanocyte development and migration

Piebaldism, WS and Tietz syndrome represent disorders of melanoblast migration or proliferation during embryonic development and are characterized by stable congenital white patches of the skin (leukoderma) and hair (poliosis or white forelock) (28) (Table 1). They are caused by mutation in various genes, including PAX3, SOX10, MITF, KIT, EDN3 and EDNRB, resulting in depigmentation due to a lack of melanocytes rather than a lack of pigment in viable melanocytes, as occurs in albinism (7).

Piebaldism

Piebaldism (MIM 17280) is a rare autosomal dominant disorder with congenital depigmented patches of the mid-forehead, chest, abdomen and extremities, where no melanocytes are found. These patches may sometimes contain hyperpigmented macules (11,12). Cutaneous depigmentation ranges from only a white forelock with minimal ventral depigmentation, to almost an entire body and hair depigmentation. Melanocytes in the eye or ear are rarely affected in this disease (6). Unlike WS, piebaldism is not accompanied by deafness and it more commonly results in white, depigmented (melanocyte-free) areas of skin rather than hair involvement. However, there have been reports of a c-Kit mutation carrier with sensorineural deafness and no cutaneous pigmentary changes, suggesting a potential overlap syndrome between piebaldism and WS (30).

In particular, piebaldism has been linked to inactivating mutations or deletions of the c-kit gene, which is mapped on chromosome 4q12, or of the SLUG gene, located on chromosome 8q11. These mutations result in decreased receptor tyrosine kinase signalling, impaired melanoblast development and a decrease in melanogenesis (6,31). Mutations of the steel factor (stem-cell growth factor), which is the ligand for c-kit result in a piebalism-like phenotype in the steel mouse, even though no such mutations have been identified in piebald patients (4,32).

The mutations of cKIT that have been identified in piebald patients range from gross deletions to missense defects, and are all inherited as autosomal dominant traits, suggesting dosage effect. Frameshift mutations that result in a null gene product produce melanoblasts with half as many cKIT receptors and thus a milder form of the disorder. By contrast, point missense mutations, specifically in the tyrosine kinase domains, produce a non-operational gene product, which reduces the signal transduction capability to one fourth and results in a more severe phenotype (32). Point missense mutations in the KIT ligand-binding domain have been identified in patients and present with extremely mild forms of piebaldism (33).

Humans with piebaldism lacking c-Kit mutations were found to have heterozygous deletions encompassing the SLUG coding region. SLUG mutation was also reported in WS2 and a mechanism proposed to account for these effects involves the binding of MITF to the SLUG promoter (34).

Waardenburg syndrome

Waardenburg syndrome (MIM 193500, MIM 193510) is an autosomal dominant genetic disorder characterized by piebaldism and sensorineural deafness. Deafness is associated with absence of neural-crest-derived melanocytes from the stria vascularis of the cochlea due to failure of melanoblasts to migrate or survive (28). The disease is commonly classified into four clinical types based on particular characteristics (Table 1).

WS1 is characterized by pigmentation and craniofacial abnormalities. The most common pigmentation abnormality is poliosis, while other less commonly encountered abnormalities include depigmented white patches of skin and pigmentary abnormalities of the iris, such as heterochromia irides (differently coloured eyes), partial heterochromia irides (variations of colour within an iris) and hypoplastic blue irides. The hallmark craniofacial defect found in virtually all WS1 patients is dystopia canthorum (widely set eyes), while a broadening of the nasal root and synophrys may be present. Congenital deafness may also exist (5). WS3 has been regarded as a variant of WS1 and presents with WS1 features with additional axial and limb musculoskeletal anomalies (28). WS type 1 and 3 result from mutations of the PAX3 transcription factor gene which has been mapped to human chromosome 2q35-q37.3 (6). The pigmentary defects of WS1 and WS3 underscore the important role of PAX3 on the expression of MITF with consequent effects on melanocyte survival during development. PAX3 also seems to be involved in the development of bony and cartilaginous structures of the face from neural crest-derived cell types as well as in skeletal development (5).

WS type 2 has been attributed to a mutation of the MITF which is located on chromosome 3p12 (6,35). Additionally, mutations in the SLUG gene have been reported, although there are cases of WS2 with no mutations in MITF or other known pigmentation genes, suggesting additional roles for yet unidentified genes. WS2 is characterized only by abnormalities associated with melanocytes. Hence, it may present with poliosis, depigmented white patches, heterochormia irides and congenital sensorineural deafness (5). This suggests that the set of genes activated by MITF is essential for developmental events subsequent to those regulated by PAX3. The restricted phenotype of WS2 may also be explained by the fact that MITF appears to be important for the development and function solely of the melanocytic lineage (5).

Patients with WS type 4 have a phenotype similar to that of WS1 but with the additional feature of Hirschsprung’s disease, which manifests with congenital aganglionic megacolon (6). Hirschsprung’s disease results from deficient neurons of the intestinal neural plexus which like melanocytes are derived form the neural crest. These patients may have a heterozygous mutation of the SOX10 gene or homozygous mutations either in the gene encoding the peptide ligand EDN3 or its receptor (EDNRB) (36,37). These genes are important determinants of the development of the neural crest-derived enteric nervous system cells that innervate the distal part of the colon (5). The transcription factor SOX10/PAX3 binds to the promoter of the MITF gene to express the MITF which in turn stimulates the expression of c-KIT. Therefore, WS4 can be a result of a defect of any one of these transcription factors that can reduce c-KIT production.

Tietz syndrome

Tietz syndrome (MIM 103500) is a rare autosomal dominant disorder, characterized by the pigmentary features of OCA (generalized depigmentation, blue eyes but no nystagmus) and the congenital deafness associated with WS. It results from mutations in the region encoding the DNA-binding domain of the MITF gene (5). Although Tietz syndrome is caused by mutation of the same gene which can cause WS2, affected patients manifest congenital, completely penetrant deafness and are not affected with heterochromia irides or patchy depigmentation (38).

Disorders of melanin synthesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Brief description of the biology of melanocytes
  5. Genetic skin hypomelanoses
  6. Disorders of melanin synthesis
  7. Disorders of melanosome formation and transfer to keratinocytes
  8. Conclusions
  9. Funding sources
  10. Conflict of interest disclosure
  11. References

Most forms of congenital hypopigmentation that are caused by defects in melanin synthesis are types of OCA and affect ocular as well as cutaneous melanocytes (6).

Oculocutaneous albinism

Albinism represents a disorder of melanocyte differentiation. Therefore, it does not result from a developmental loss of pigment cells, but from their inherited dysfunction resulting in complete or partial loss of cutaneous pigmentation (5). The absence or severe dysfunction of tyrosinase and other key pigment enzymes (including P gene, TRP1 and MATP) results in OCA types 1–4, which presents with melanocytes that are intact but unable to make pigment (19).

Inherited by an autosomal recessive disorder, OCA is characterized by hypomelanosis in most tissues including the skin, hair and eyes, accompanied by reduced visual acuity with nystagmus and photophobia (Table 2). It affects approximately 1 in 20000 individuals. Defects in the melanin biosynthesis or transport result in a deficiency or complete absence of melanin in affected patients. Although there are six types of OCA, other disorders such as HPS, CHS, GS are commonly classified into a group of OCA, and are thought to represent OCA with systemic manifestations (4,5). Ocular nystagmus is a hallmark of all forms of OCA with or without systemic involvement (5).

In patients with OCA1A (tyrosinase-negative OCA, MIM 203100), tyrosinase activity is completely lacking due to a mutation of its encoding gene (TYR), which has been mapped at 11q14–21 (6). Melanin formation does not occur throughout the patient’s life, because the first step of melanin synthesis is blocked. Therefore, OCA1A phenotype is characterized by completely white hair, pinkish skin and red pupils (4).

Patients with OCA1B (yellow-mutant OCA, MIM 606952) completely lack detectable pigment at birth and are initially indistinguishable from patients with tyrosinase-negative OCA (OCA1A). However, such patients rapidly develop yellow hair pigment in the first few years of life and then continue to slowly accumulate pigment in the hair, eyes and skin. In these patients, tyrosinase activity is greatly decreased but not completely absent. A point mutation in the tyrosinase gene causes a small change in the tyrosinase conformation, or causes the formation of a new splicing site associated with decreased enzyme activity (39,40).

Patients with temperature-sensitive OCA (OCA1TS, MIM 606952) have white hair and skin and blue eyes at birth. At puberty, they develop progressively darker hair at cooler areas of the body (extremities) but retain white hair in the warmer areas (scalp, axilla) (41). A missense mutation in the tyrosinase gene of such patients causes one amino acid replacement which makes the enzyme temperature-sensitive, with very low activity at 35°C and loss of activity above 35°C (42).

Oculocutaneous albinism 2 results from loss-of-function mutations of the P gene, which is located on chromosome 15q11–12 (6). It encodes a melanosomal membrane protein that may regulate processing and transport of tyrosinase (28). More than 40 P gene mutations have been reported in tyrosinase-positive OCA2 (MIM 203200). The phenotypes of OCA2 are variable. Patients with complete loss of melanin are indistinguishable from patients with OCA1A, while those with brown hair resemble OCA1B patients (4). The specific function of P protein in the melanocyte has not been fully clarified. It has been proposed that both P and MATP protein (a disease-responsible protein for OCA4) seem to function by directing the traffic of melanosomal proteins (including tyrosinases) to the melanosome (43). In addition, albinos with P gene mutation, who would be expected to have yellow hair, may have red hair if MC1R mutations co-exist (22).

Oculocutaneous albinism 3 (MIM 203290) or TRP1 gene-related OCA, or Rufous OCA, has been described exclusively in South African blacks and is caused by mutations in the TRP-1 gene, which is located at 9p23 (6,28). TRP1 protein has 5,6-dihydroxyindole-2-carboxylic acid (DHICA) activity, which catalyses the polymerization of DHICA. The minimally hypopigmented phenotype of OCA3 patients is the reason why no OCA3 patient has been reported in other ethnic groups (4).

Oculocutaneous albinism 4 (MIM 606574) results from mutations of the MATP gene and is considered one of the most common forms of OCA in Japan. This is the human homologue of mouse under-white (uw) gene, which has been known to cause generalized hypopigmentation (28). The function of MATP in humans seems to involve intracellular processing and trafficking of melanosomal proteins. Single nucleotide polymorphisms in the MATP gene have been shown to have a role in normal hair, skin and eye pigmentation (44,45). A homozygous G to A transition in the splice acceptor sequence of exon 2 of MATP gene has been reported (46). The clinical phenotype of OCA4 reported in Japanese patients is variable and similar to OCA2. OCA4 albinism is rare in Caucasian patients (4).

Disorders of melanosome formation and transfer to keratinocytes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Brief description of the biology of melanocytes
  5. Genetic skin hypomelanoses
  6. Disorders of melanin synthesis
  7. Disorders of melanosome formation and transfer to keratinocytes
  8. Conclusions
  9. Funding sources
  10. Conflict of interest disclosure
  11. References

Perturbations in specific steps during the formation, maturation and trafficking of melanosomes, may produce clinically recognizable phenotypes such as Hermansky-Pudlak Syndrome (HPS), CHS and GS (Table 3) (29).

Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome (MIM 203300) is a genetically heterogeneous group of related autosomal recessive conditions described in humans and mice. There are eight known human HPS genes causing different subtypes of HPS (HPS 1–8) and at least 14 murine HPS genes, eight of which are orthologous to the human genes (29). Defects in proteins encoded by these genes can affect the biogenesis and/or function of intracellular organelles found in specialized secretory cells such as pigment cells (melanocytes and retinal pigment epithelial cells), platelets, T cells, neutrophils and lung type II epithelial cells. The organelles affected by HPS genes belong to the family of organelles known as lysosome-related organelles (29).

HPS is a form of albinism with extrapigmentary disorders. The pigment phenotype of HPS patients is extremely variable and can range from a minimal to a severe reduction in skin, hair and ocular pigmentation. In general, there is no tanning response after sunlight exposure in these patients (6). While all HPS patients suffer from OCA and prolonged bleeding, different subtypes with distinguishing features have been recognized (Table 3) (29).

Mutations in two HPS genes namely HPS1 and HPS4 [murine orthologs are pale ear (ep) and light ear (le) respectively] cause the most common and most severe clinical subtypes, in which affected individuals have oculocutaneous albinism, prolonged bleeding (due to platelet storage pool deficiency) and can suffer morbidity from granulomatous colitis and premature mortality from pulmonary fibrosis (29).

The human HPS1 gene has been mapped on chromosome 10q23.1–q23.3. The most common HPS-1 mutation is found in Puerto Rican patients and is caused by a 16-bp frameshift duplication in exon 15 (29). HPS-1 protein is ubiquitous and primarily localized to the cytosol, with a small proportion being membrane-associated. It appears to play a role in regulating protein traffic targeted to the melanosome. In melanocytes derived from HPS-1 patients, immunostaining for tyrosinase, TYRP1 and TRP2/DCT produced a pattern with large vesicular structures in the cell body and dendrites, instead of a small granular pattern seen throughout the control cells (melanocytes from unaffected individuals) (47).

The HPS4 gene is located on chromosome 22q11.2-q12.2. As in other subtypes of HPS, HPS-4 patients have great variability in the degree of hypopigmentation, and may present with a severe phenotype, similar to that of HPS-1 patients (29).

The similarity in phenotypes between HPS-1 and HPS-4 subtypes and between ep and le mice is explained by the finding that intracellular HPS-1 and HPS-4 proteins associate together in a protein complex termed biogenesis of lysosome-related organelle complex (BLOC-3), as do the ep and le proteins (48). BLOC-3 complex regulates the biogenesis and/or function of the lung lamellar body as well as the platelet dense body and the melanosome (29).

A study in the ep mouse strain suggested that regulation of melanocytes differs in follicles versus interfollicular skin. Alternatively, melanocytes in different anatomic units (e.g. back versus tail) are differentially regulated. These findings underscore the role of HPS1 gene in influencing the developmental fate of melanocytes. They may also offer a possible explanation for the disassociation of pigment phenotype which is observed in people with dark hair but fair skin (49).

HPS-2 is caused by mutations in the AP3B1 gene encoding the β3A subunit of the heterotetrameric adaptor protein complex AP-3. AP-3 plays a role in mediating cargo protein selection into transport vesicles and in trafficking those membrane proteins to the lysosome (28,29). Τhe HPS-2 subtype may be clinically distinguished from the other forms of HPS, as it is unique in causing immunodeficiency and manifesting with neutropenia and susceptibility to recurrent respiratory illnesses. It may be differentiated from CHS, as large intracellular granules which are seen in CHS, are not present in HPS-2 (29).

The HPS-3, HPS-5 and HPS-6 subtypes are clinically similar. They may present with ocular albinism and bruising, but without pulmonary fibrosis or colitis.

The HPS3 gene is found on chromosome 3q24. HPS-3 protein associates with HPS-5 and HPS-6 proteins in a multimeric protein complex, BLOC-2. Immunofluorescent imaging of melanocytes derived from HPS-3 patients demonstrated that molecules normally targeted to later stage melanosomes (e.g. the melanogenic enzymes tyrosinase and Tyrp1) are mislocalized. By contrast, the steady-state distribution of molecules targeted to stage I melanosomes (e.g. silver/Pmel17/gp100 and melan-a/MART1) were found to be normal. DOPA staining detected melanogenic enzymatic activity in melanosomes, suggesting that melanogenic enzymes can accesss melanosomes via an HPS-3-independent pathway. In addition, it has been suggested that the lack of detected melanin in later stage melanosomes in HPS-3 cells is due to the limiting quantity of another (presumably mis-trafficked) molecule (29,50).

HPS-5, a rare type of HPS, results from mutations in HPS5 gene which is located on chromosome 11p14 (29). It encodes a cytoplasmic protein of unknown function that interacts with the HPS-6 protein (gene locus on chromosome 10q24.32) (28). All HPS-5 patients have been reported to have elevated cholesterol levels, with several having mildly elevated triglycerides as well. The significance of these elevated lipid levels and whether they are a result of an underlying membrane trafficking defect, is not known (29).

The DTNBP1 gene which is defective in HPS-7 is located on chromosome 6p22.3 and encodes the dysbindin protein. A single patient reported with HPS-7, presented with oculocutaneous albinism, easy bruisability, bleeding tendency and a decreased lung compliance (29). Finally, in patients with HPS-8, the defective gene is BLOC1S3. Patients present with OCA and mild platelet dysfunction with easy bruising, epistaxis and a bleeding tendency (29).

Chediak-Higashi syndrome

Chediak-Higashi syndrome (MIM 214500) is a rare autosomal recessive disorder characterized by OCA (extensive depigmentation of skin, hair and eyes) and a silvery sheen to the hair. It is also characterized by a bleeding tendency, progressive primary neurological impairment and severe immune deficiency due to lack of natural killer cell function, resulting in recurrent pyogenic infection. Additionally, it causes a severe haemophagocytic lymphoproliferative syndrome caused by uncontrolled T-cell and macrophage activation. CHS is characterized by massive cytoplasmic lysosomal and non-lysosomal inclusions in granule containing cells, which are probably responsible for most of the impaired functions in CHS cells. Melanocytes containing giant melanosomes seem to account for the hypopigmentation (6). Most cases are fatal unless treated by bone marrow transplantation (28).

Chediak-Higashi syndrome has been linked to the human gene CHS1/LYST, which is homologous to the beige locus in mouse and is located on chromosome 1q43 (6,51). The CHS1 protein is predicted to be a cytosolic protein with a role in vesicular transport. It is similar to HSP proteins, since the presence of giant granules within various vesicles such as lysosomes, melanosomes, cytosolic granules and platelet dense bodies is also observed in various cells of CHS patients (4).

Griscelli syndrome

Griscelli syndrome is a rare autosomal recessive disorder characterized by pigmentary dilution of the skin, a silver-grey sheen of the hair, large clumps of pigment within hair shafts and the accumulation of large and abnormal end-stage melanosomes in the centre of melanocytes (52). The disease has been linked with defects of the Rab27a-Mlph-MyoVA protein complex formation in melanocytes, which is important to keep melanosomes connected to the actin network (52).

Patients with GS can be categorized in 3 types. Type 1 (GS1-MIM214450) is manifested with albinism, and severe primary neurological impairment, with developmental delay and mental retardation. It has been attributed to mutations of the myosin 5A gene (MYO5A) which encodes an organelle motor protein, myosin VA (53).

Griscelli syndrome-Type 2 (GS2-MIM 607624) presents with albinism and is associated with potentially lethal immune defects and a haemophagocytic syndrome. Bone marrow transplantation is the only curative treatment. GS2 is caused by mutations in RAB27A which encodes a small GTPase protein (Rab27a), involved in the function of the intracellular-regulated secretory pathway (53).

Griscelli syndrome 3 results from mutation in the gene that encodes melanophilin (MLPH). Unlike GS1 and GS2, GS3 has only dermatological manifestations (4). Deletion of MYO5AF exon may result in an identical phenotype without neurological manifestations.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Brief description of the biology of melanocytes
  5. Genetic skin hypomelanoses
  6. Disorders of melanin synthesis
  7. Disorders of melanosome formation and transfer to keratinocytes
  8. Conclusions
  9. Funding sources
  10. Conflict of interest disclosure
  11. References

More than 100 genes are involved in the process of melanogenesis, encoding important structural, enzymatic and regulatory proteins (54). Alterations in the transcription, translation, processing or intracellular trafficking of any of these genes/proteins might affect melanin synthesis. In addition, the transfer of melanosomes from melanocytes to keratinocytes and their break-down in keratinocytes are processes that play important roles in the regulation of pigmentation in the skin and hair (55).

Although numerous pigmentation mutants are phenotypically profound, they have not yet been fully clarified (3). Genodermatoses with pigmentary abnormalities highlight several genetic features that are instructive with regard to melanocyte biology and that may shed new light on pathways influencing human pigmentation and its associated disorders.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Brief description of the biology of melanocytes
  5. Genetic skin hypomelanoses
  6. Disorders of melanin synthesis
  7. Disorders of melanosome formation and transfer to keratinocytes
  8. Conclusions
  9. Funding sources
  10. Conflict of interest disclosure
  11. References