genetics of pigmentary disorders

American Journal of Medical Genetics Part C (Semin. Med. Genet.) 131C:75–81 (2004)

A R T I C L E

Genetics of Pigmentary DisordersYASUSHI TOMITA* AND TAMIO SUZUKI

The genetic and molecular bases of various types of congenital pigmentary disorders have been classified in thepast 10 years, as follows: (1) disorders of melanoblast migration in the embryo from the neural crest to the skin:piebaldism; Waardenburg syndrome 1–4 (WS1–WS4); dyschromatosis symmetrica hereditaria. (2) Disordersof melanosome formation in the melanocyte: Hermansky–Pudlak syndrome 1–7 (HPS1–7); Chediak–Higashisyndrome 1 (CHS1). (3) Disorders of melanin synthesis in the melanosome: oculocutaneous albinism 1–4 (OCA1–4). (4) Disorders of mature melanosome transfer to the tips of the dendrites Griscelli syndrome 1–3 (GS1–3).These disorders are presented and their gene mutations and pathogenesis are discussed. � 2004 Wiley-Liss, Inc.

KEY WORDS: albinism; Chediak–Higashi syndrome; dyschromatosis; Griscelli syndrome; Hermansky–Pudlak syndrome; piebaldism;Waardenburg syndrome

INTRODUCTION

Melanin is synthesized in the melano-

somes ofmelanocytes located in the basal

layer of the epidermis and in the hair

bulb. Mature melanosomes, after their

synthesis in the perikaryon of the mela-

nocyte are transferred to the tips of its

dendrites and are released into keratino-

cytes. Congenital pigmentary disorders

are due to various gene mutations that

cause defects in melanin synthesis, for-

mation of the melanosomes, their trans-

fer within the melanocyte, as well as

melanocyte maldevelopment.

In 1989, we reported for the first

time a pathological mutation of the

tyrosinase gene of a patient with oculo-

cutaneous albinism (OCA) [Tomita

et al., 1989]. Since then, various genes

responsible for congenital pigmentary

diseases have been reported. Since the

space allocated for this review does not

permit all disorders of pigment synthesis

and transport, we have categorized them

as follows and chosen representative

conditions for discussion (Table I): (1)

disorders of melanoblast migration in

the embryo from the neural crest to the

skin. (2) Disorders of the melanosome

formation in the melanocyte. (3) Dis-

orders of the melanin synthesis in

the melanosome. (4) Disorders of

mature melanosme transfer to the tips

of the dendrites.

DISORDERS OFMELANOBLASTMIGRATION FROMTHE NEURAL CREST

Piebaldism (MIM 17280)

Piebaldism is an autosomal dominant

disorder with hypopigmented patches

on the midforehead, chest, abdomen,

and extremities where no melanocytes

are found. Giebel and Spritz [1991] and

Fleischman et al. [1991] discovered

mutations in the KIT gene encoding a

plasmamembrane receptor for the stem-

cell growth factor involving melanoblast

proliferation and migration. The reduc-

tion in receptors impairs the survival and

migration of the neural crest-derived

melanoblasts, resulting in failure of their

colonization at anatomic sites most

distant from the neural crest.

The steel mouse lacks steel factor,

the ligand for kit, in other words, the

stem-cell growth factor. Therefore, the

phenotype of steel mouse is similar to

piebaldism, but no piebald patient with a

defect of the stem-cell growth factor has

been found yet.

Waardenburg Syndrome

(MIM 193500, 193510)

Waardenburg syndrome (WS) is an

autosomal dominant genetic disease

characterized by piebaldism, certain

characteristic facial feature, heterochro-

mia irides, and sensorineural deafness. It

is commonly classified into four clinical

types defined by the presence of addi-

tional signs as shown in Table II.

Type 1 and 3 patients have a muta-

tion of the PAX3 transcription factor

gene [Baldwin et al., 1992; Tassabehji

et al., 1992]. Type 2 is due tomutation of

the gene for a micropthalmia associated

transcription factor (MITF) [Tachibana

et al., 1994; Tassabehji et al., 1994]. Type

4 patients have a heterozygous mutation

of the SOX10 gene or homozygous

mutations either in the Endothelin-3

(EDN3) or in the Endothelin B receptor

(EDNR3) gene [Puffenberger et al.,

1994; Mccallion and Chakravarti, 2001].

There are epistatic relationships

between SOX10/PAX3 and MITF, and

Dr. Yasushi Tomita is a professor andchairman of Department of Dermatology atNagoya University Graduate School of Med-icine. He has been studying on melanocyte,melanoma, and pigmentary disorders.

Dr. Tamio Suzuki is an associate professorof Department of Dermatology at NagoyaUniversity Graduate School of Medicine.He has a strong research interest in geneticsof inherited pigmentary disorders, i.e., ocu-locutaneous albinism, Hermansky–Pudlaksyndrome.

*Correspondence to: Yasushi Tomita,Department of Dermatology, Nagoya Uni-versity Graduate School of Medicine, 65Tsurumai, Showa-ku, Nagoya 466-8550,Japan. E-mail: [email protected]

DOI 10.1002/ajmg.c.30036

� 2004 Wiley-Liss, Inc.

between MITF and c-KIT. As shown

in Figure 1, the transcription factor

SOX10/PAX3 binds to the promoter

of the MITF gene to express the MITF

[Tachibana, 1999] which stimulates the

expression of c-KIT. Alternatively, a de-

fect of any one of these three trans-

cription factors can reduce the c-KIT

production, which consequently indu-

ces piebaldism.

DYSCHROMATOSISSYMMETRICAHEREDITARIA (MIM 127400)

Dyschromatosis symmetrica hereditaria

(DSH) (also called acropigmentation

symmetrica of Dohi) is an autosomal

dominant disease and is characterized by

a mixture of hypo- and hyper-pigmen-

ted macules of various sizes on the dorsa

of the hands and feet. This conditionwas

first described by Toyama in 1910 and,

since then, many patients have been

reported not only in Japan but also from

many other ethnic groups. Recently, we

have performed a genomewide search in

three families with DSH, and have

determined that mutations in the gene

of double-stranded RNA-specific ade-

nosine deaminase (DSRAD), one of the

RNA-editing enzymes are responsible

for this condition [Miyamura et al., 2003].

The reason why a low activity of

DSRAD induces the peculiar skin

lesions localized specifically on the dorsa

of hands and feet is at present unknown.

We speculate that, when melanoblasts

migrate from the neural crest to the skin

during development, a greater reduction

in DSRAD activity might occur at anato-

mic sitesmost distant from theneural crest.

DISORDERS OFMELANOSOMEFORMATION IN THEMELANOCYTE

Hermansky–Pudlak Syndrome

(MIM 203300)

Hermansky–Pudlak syndrome (HPS),

inherited as an autosomal recessive trait,

is clinically characterized by a triad of

features: (1) OCA, (2) mild to severe

bleeding diathesis, and (3) ceroid storage

disease. These manifestations result from

an abnormal formation of intracellular

vesicles, i.e., a dysfunction of melano-

somes results in OCA, and absence of

platelet dense bodies causes a bleeding

diathesis. As shown in Table III, seven

genes responsible for HPS are presently

known [Oh et al., 1996; Dell’Angelica

et al., 1999; Anikster et al., 2001; Suzuki

et al., 2002; Li et al., 2003; Zhang et al.,

2003]. Their respective proteins con-

tribute to the biogenesis of membrane

organella such as melanosomes (Fig. 2)

and lysosomes. For example, the gene

for HPS2, ADTB3A (adaptor-related

protein complex 3), encodes the beta 3A

subunit of heterotetrameric complex

AP-3 (adaptor protein-3). Adaptor

complexes play a role in the formation

of coated vesicle, as well as in the

selection of cargo for these vesicles

[Clark et al., 2003].

There are 16 mouse models of HPS

in which homologs of human 7 types of

HPS are included [Huizing et al., 2002;

Li et al., 2003]. Therefore, many other

genetic types of HPS will likely be

reported in the future.

Chediak–Higashi Syndrome

(MIM 214500)

Chediak–Higashi syndrome (CHS) is an

autosomal recessive disorder characterized

TABLE I. Genetic Pigmentary

Disorders

1. Disorders of melanoblast

migration from the neural crest

into the skin

Piebaldism

Waardenburg syndrome (WS)

Dyschromatosis symmetrica

hereditaria

2. Disorders of melanosome

formation in the melanocyte

Hermansky–Pudlak syndrome

Chediak-Higashi syndrome

3. Disorders of melanin synthesis in

the melanosome

Oculocutaneous albinism (OCA)

4. Disorders of mature melansome

transfer to the tips of dendrites

Griscelli syndrome

TABLE II. Type of Waardenburg Syndrome

Type MIM# Gene Hereditary Particular characteristics

I: WS1 193500 PAX3 AD White forelock and skin patches more

frequent

Dystopia canthorum present

II: WS2 193510 MITF AD No dystopia canthorum.

600193 Sensorineural hearing loss and

606662 heterochromia irides more frequent

III: WS3 148820 PAX3 AD Dystopia canthorum and limb

anomalies

IV: WS4 277580 SOX10 AD Aganglionic megacolon

Dyschromatosis symmetrica

hereditaria (DSH)

(also called acropigmentation

symmetrica of Dohi) is an

autosomal dominant disease

and is characterized by a

mixture of hypo- and

hyper-pigmented macules of

various sizes on the dorsa of

the hands and feet. We have

determined that mutations in

the gene of double-stranded

RNA-specific adenosine

deaminase (DSRAD), one of

the RNA-editing enzymes are

responsible for this condition.

76 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE

by severe immune deficiency, OCA,

bleeding tendencies, recurrent pyogenic

infection, progressive neurologic defects,

and a lymphoproliferative syndrome.

OCA observed in these patients have

dilute pigmentation and the hair is often

silvery or steely gray.

The human causative gene,CHS1/

LYST has been reported by Nagel et al.

[1996] and shown to be homologous to

the beige locus in mouse. CHS1 protein

is predicted to be a cytosolic protein

with a role in vesicle transport (Fig. 2). It

is similar to HPS proteins, because the

presence of giant granuleswithin various

vesicles such as lysosomes, melano-

somes, cytosolic granules, and platelet

dense bodies, is observed in various cells

of CHS patients.

DISORDERS OF MELANINSYNTHESIS

OCA is an autosomal recessive disorder

characterized by hypomelanosis in most

tissues including the skin, hair, and eyes,

accompanied by reduced visual acuity

with nystagmus and photophobia. It is

caused by a disturbance in melanin

polymer synthesis in the melanosome.

Although there are six different

types of OCA (Table IV), HPS, CHS,

and Griscelli syndrome are usually clas-

sified into a group of OCA. They are

reviewed here in the sections describing

disorders of melanosome formation and

those of mature melanosome transfer in

the melanocyte.

OCA1A (MIM 203100)

In patients with OCA1A (tyrosinase-

negative OCA), tyrosinase activity is

completely lacking due to mutation in

its gene. Melanin formation does not

occur throughout the patient’s life,

because the first step of melanin syn-

thesisis blocked (Fig. 2). Therefore, its

In patients with OCA1A

(tyrosinase-negative OCA),

tyrosinase activity is

completely lacking due to

mutation in its gene. Melanin

formation does not occur

throughout the patient’s life,

because the first step of

melanin synthesis is blocked.

phenotype is characterized by comple-

tely white hair, pinkish skin, and red

pupils. Since the first report by Tomita

et al. [1989], more than 90 mutations

causing OCA have been reported by

various groups [Oetting andKing, 1999].

OCA1B (MIM 606952)

Patient with OCA1B (yellow-mutant

OCA) completely lack detectable pig-

ment at birth and are initially in-

distinguishable from patients with

tyrosinase-negative OCA. 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 patient, tyrosinase activity is

greatly deceased but not completely

absent. A point mutation in the tyrosi-

nase gene causes a small change in the

tyrosinase conformation [Giebel et al.,

1991a] or causes the formation of new

splicing site [Matsunaga et al., 1999],

which must be the cause of the great

decrease in enzyme activity.

The genotype of a 1B patient is

homoalleic for 1B allele or is hetero-

zygotic for 1B and 1A alleles.

OCA1TS (MIM 606952)

Patients with temperature-sensitive

OCA (OCA1TS) have white hair and

Figure 1. A cascade of genes and their products related to Waadenburg syndrome.Transcription factors of PAX3 and SOX10 epistatically upregulate a gene expression of atranscription factor of MITF which stimulate the synthesis of c-KITas well as tyrosinaseand TRP-1. Conversely, c-KIT involves activation of MITF.

TABLE III. Types of Hermansky–Pudlak Syndrome (HPS)

Type MIM# Gene

Symptomes

OCA

Bleeding

disorder

Pulmonary

fibrosis Colitis

HPS1 203300 HPS1 þþþ þþþ þþþ þþ604982

HPS2 608233 ADTB3A þþ þ ? ?

HPS3 606118 HPS3 þ þ þ/� þþHPS4 606682 HPS4 þþþ þþþ þþþ þþHPS5 607521 HPS5 þ þþ ? ?

HPS6 607522 HPS6 þþ þþ � �HPS7 607145 DTNBP1 þþþ þþþ � ?

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 77

skin, and blue eyes at birth. At puberty,

they develop progressively darker hair in

the cooler areas of the body (extremities)

but retain white hair in the warmer areas

(scalp and axilla) [King et al., 1991]. A

missense mutation in the tyrosinase gene

of such patients causes one amino acid

replacement which makes the enzyme

temperature sensitive, i.e., with very low

activity at 358C and loss of activity above

358C [Giebel et al., 1991b]. The geno-

type of a 1TS patient is homoalleic for

1TS allele or heterozygotic for 1TS and

1A alleles.

OCA2 (MIM 203200)

Rinchik et al. [1993] reported a muta-

tion in the human P gene in a case of

tyrosinase-positive OCA, which was

later classified as OCA2. At present,

more than 40 P gene mutations causing

OCA2 are known [Oetting and King,

1999]. The phenotypes of OCA2 are

variable, i.e., a patientwith complete loss

of melanin is indistinguishable from an

OCA1A patient and one with brown

hair resembles an OCA1B patient.

The specific function of the P

protein in the melanocyte is not been

fully clarified. Lee et al. [1995] reported

that the 838-amino-acid protein con-

tains 12 transmembrane domains similar

to various transporters and appears to be

an integral membrane protein of mela-

nosomes (Fig. 2). Kushimoto et al.

[2003] 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 melano-

some (Fig. 2).

OCA3 (MIM 203290)

Tyrosinase-related protein 1 (TRP-1)

was demonstrated to have 5,6-dihydrox-

Figure 2. Melanin synthesis in the melanosome. Melanosomal protein are transported by specialized sorting vesicles throughendosomes or directly to melanosomes. Hermansky–Pudlak syndrome (HPS) and Chediak–Higashi syndrome (CHS) proteins arecomponents of the vesicles. Melanin is formed from tyrosine by enzymes of tyrosinase, tyrosinase-related protein 2 (TRP2)/dopachrometautomerase (Dct) and TRP1/DHICA oxidase in the melanosome. P protein and membrane-associated transporter (MATP) are suspectedto be a cationic-ion and sucrose transporters, respectively. Tyrosinase, P protein, TRP1, andMATPare responsible proteins forOCA1, 2, 3,and 4, respectively.

TABLE IV. Types of Oculocutaneous Albinism (OCA)

Type MIM# Gene Hair color at birth

OCA1 TYR

OCA1A 203100 White

OCA1B 606952 White, blond, light brown

OCATS 606952 Light brown, brown

OCA2 203200 P White, blond, light brown

OCA3 203290 TRP1 Light brown

OCA4 606574 MATP White, blond, light brown


yindole-2-carboxylic acid (DHICA)

oxidase activity, which catalyzes the

polymerization of DHICA (Fig. 2).

Boissy et al. [1996] reported that a

homozygous mutation for TRP-1 gene

of African-American twin responsible

for the decreased melanogenesis. And

Manga et al. [1997] clarified that Rufous

OCA in African blacks is caused by

mutations in the TRP1 gene. Rufous

OCA is now classified as TRP-1 gene-

related OCA or OCA3. Clinical feature

of OCA3 is rather mild, judging from

light brown of the patient’s skin com-

pared to the dark brown skin of their

parents in southern African blacks. The

mild phenotype may prevent the detec-

tion of OCA3 patients, which is the

reason why no OCA3 patients has been

reported from other ethnic populations.

TRP-2 protein has dopachrome

tautomerase activity (Fig. 2). No muta-

tion of the human dopachrome tauto-

merase (TRP-2) gene-related OCA has

been reported yet.

OCA4 (MIM 606574)

OCA4 has been recently classified as a

new type of OCA. The mouse under-

white (uw) gene has been known to

cause generalized hypopigmentation.

The human homologue of mouse uw is

a membrane-associated transporter pro-

tein gene (MATP) (Fig. 2). The function

of MATP in the human has not been

clarified yet, but it is suspected to be a

sucrose transporter or to be similar to the

P protein.Newton et al. [2001] reported

a homozygous G to A transition in the

splice acceptor sequence of exon 2 of

MATP gene in a Turkish OCA patient,

and the MATP gene was recognized

as the fourth one causing OCA. This

type of patient may be rare among

Caucasians, since few patients have been

reported since the first case.

We have found 17 Japanese OCA4

patients with seven novel mutations

including four missense, two deletion

and one insertion mutations [Tomita

et al., 2003]. According to our survey of

Japanese patients, almost a half of OCA

patients belongs toOCA1, and the other

half is comprised of OCA2 (10%),

OCA4 (25%) and unclassified (15%).

OCA4 is therefore one of major type in

Japan. The clinical phenotype of Japa-

neseOCA4 is variable and similar to that

of OCA2.

A DISORDEROF MATUREMELANOSOME TRANSFERIN THE MELANOCYTE

Griscelli Syndrome

Griscelli syndrome (GS) is a rare auto-

somal recessive disorder characterized by

pigmentary dilution of the skin, a silver-

gray sheen of the hair, the presence of

large clumps of pigment in the hair

shafts and the presence of large clumps

of pigment in the hair shaft, and an

abnormal accumulation of end-stage

melanosomes in the center of melano-

cytes [Pastural et al., 1997; Menasche

et al., 2003].

Three types of GS have

been described.

Three types of GS have been

described. All three have typical derma-

tological characteristics. In addition to

the characteristic albinism type 1 (GS1-

MIM214450) is associated with severe

primary neurological impairment with

developmental delay andmental retarda-

tion. It is caused by mutations of the

myosin 5A gene (MYO5A) which

encodes an organelle motor protein,

Myosin VA (MyoVA) [Pastural et al.,

1997] (Fig. 3).

The second type (GS2: MIM

607624) is associated with an immune

defect, whichmay cause life-threatening

episodes of uncontrolled T lymphocyte

andmacrophage activation, and a hemo-

phagocytic syndrome. Bone marrow

transplantation is the only curative treat-

ment for this condition [Blanche et al.,

1991]. GS2 is caused by mutations in

RAB27Awhich encodes a small GTPase

protein (Rab27a), involved in the func-

tion of the intracellular-regulated secre-

tory pathway [Menasche et al., 2000]

(Fig. 3).

The third type of Griscelli syn-

drome (GS3) results from mutation in

the gene that encodes melanophilin

(MLPH). GS3 has only dermatologic

manifestations, unlike GS1 and GS2.

Moreover, it has been noted that an

identical phenotype, without neurolo-

gical manifestation, can result from the

deletion of theMYO5AF-exon. It is thus

concluded that, without the Rab27a-

Mlph-MyoVA protein complex forma-

tion in melanocytes (Fig. 3), melano-

somes cannot be connected to the action

network and transported toward the tips

TABLE V. Type of Griscelli Syndrome (GS)

Type Gene Characteristics

GS1 MY5A Pigmentary dilution of skin and hair

Neurologic manifestations

GS2 RAB27 Pigmentary dilution of skin and hair

Immune defects and hemophagocytic syndrome

GS3 MLPH Only pigmentary dilution of skin and hair

Griscelli syndrome (GS) is

a rare autosomal recessive

disorder characterized by

pigmentary dilution of the

skin, a silver-gray sheen of

the hair, the presence of large

clumps of pigment in the hair

shafts and an abnormal, the

presence of large clumps of

pigment in the hair shaft, and

an abnormal accumulation of

end-stage melanosomes in the

center of melanocytes.


of the melanocytes. [Westbroek et al.,

2001; Menasche et al., 2003].

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Figure 3. Shema of the heterotrimeric protein complex involved in melanosometransport.Maturemelanosomes around the nucleus are transported on the actin filamentsto the peripheral tips of the dendrites and are delivered to the surrounding keratinocytes.A complex ofMyo-VA,Mlph, andRab27a interacts between amelanosome and an actinfilament.Myo-VAhasmolecular motors, i.e., ATPasesmoving along the actin filament ofthe cytoskeleton. A defect in the proteins of Myo-VA, Mlph, and Rab27a leads to GS1,GS2, and GS3, respectively. (From Menasche et al., 2003 with modification).


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genetics of pigmentary disorders

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