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Chapter 20: Pigmentation and Melanocyte Biology

Stephen M. Ostrowski; David E. Fisher

AT-A-GLANCE

AT-A-GLANCE

  • Development of Melanocytes

    • Melanocytes are derived from neural crest lineage

    • Transcription factors (MITF, SOX10, PAX3) and signaling pathways (KIT, EDNRB) that are important for development, migration, and survival of melanocytes also play key roles in melanoma

  • Function of melanocytes

    • Key function of melanocytes is to synthesize melanin and transfer to surrounding keratinocytes

    • Melanocytes can produce brown/black melanin (eumelanin) or orange/yellow melanin (pheomelanin)

    • The melanosome, a specialized lysosome-related organelle, is the site of melanin synthesis and storage

  • Regulation of human pigmentation

    • Common human variants in melanocortin 1 receptor (MC1R) lead to the “red hair phenotype”—red hair, fair skin, inability to tan, and increased melanoma risk

    • MC1R signals to the MITF transcription factor to regulate pigmentation and sun-tanning

INTRODUCTION

Melanocytes are specialized cells of the epidermis and hair follicle whose primary function is to synthesize and transfer melanin to adjacent keratinocytes. Melanin synthesis occurs in a specialized organelle, the melanosome; proper melanosome biogenesis and trafficking are required for normal pigmentation. Melanocyte numbers are similar in individuals of different racial backgrounds, and instead differences of pigmentation are a result of the amount and quality of melanin in the skin, in large part driven by variability in the number, size, distribution, and function of melanosomes within keratinocytes.1,2 Analysis of mutations in mice and humans (Table 20-1) that cause pigmentation defects have allowed the identification of key regulators of melanocyte development, survival, and function. Many of these same genes play critical roles in the pathogenesis of melanoma.

Table 20-1Genetic Hypopigmentation and Hyperpigmentation Disorders Caused by Mutations in Genes Important for Melanocyte Development and Biology
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Table 20-1 Genetic Hypopigmentation and Hyperpigmentation Disorders Caused by Mutations in Genes Important for Melanocyte Development and Biology
DISORDER GENE MUTATION CLINICAL FEATURES
Hypopigmentation disorders
Ocular albinism (OA1) GPR143 Reduced pigmentation of iris and retina; photosensitivity; decreased visual acuity; nystagmus; strabismus; misrouting of optic nerve
Oculocutaneous albinism  

Cutaneous albinism (pigmentary dilution of skin and hair)

Ocular albinism (see above)

  • OCA1

 TYR

OCA1A: tyrosinase-negative (severe) albinism (complete loss of tyrosinase function)

OCA1B: tyrosinase-positive (mild to moderate) albinism

  • OCA2

 OCA2 “Brown” albinism

  • OCA3

 TYRP1 “Rufous” albinism

  • OCA4

 SLC45A2/MATP Variable degrees of albinism
Waardenburg Syndrome   Piebaldism, congenital deafness, heterochromia irides, synophrys, broad nasal root, dystopia canthorum

  • WS1

 PAX3 Classic type

  • WS2

MITF

SNAI2

 Lacks dystopia canthorum

  • WS3

 PAX3 Limb abnormalities (hypoplasia, syndactyly)

  • WS4

SOX10

EDN3

EDNRB

 Hirschsprung disease
Tietz syndrome MITF Tyrosinase-positive cutaneous albinism; deafness; eyebrow hypoplasia
Piebaldism cKIT Depigmented forelock and abdominal skin
Hermansky-Pudlak syndrome (HPS)  

Tyrosinase-positive oculocutaneous albinism (melanosome dysfunction)

Bleeding diathesis (platelet granule dysfunction)

Interstitial pulmonary fibrosis (HPS 1,2,4), granulomatous colitis (HPS 1,4), renal failure (rare), cardiomyopathy (rare) (caused by ceroidal lipofuscin accumulation in lysosomes)

Neutropenia and cytotoxic T-cell dysfunction (HPS2)

  • HPS1

 HPS1 (BLOC-3)  

  • HPS2

 AP3B1 (AP-3)  

  • HPS3

 HPS3 (BLOC-2)  

  • HPS4

 HPS4 (BLOC-3)  

  • HPS5

 HPS5 (BLOC-2)  

  • HPS6

    ...

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