Chapter 220

## Abstract

Abstract  Note to Readers: Human gene symbols are all uppercase italics (e.g., TYR); murine gene symbols are first letter uppercase, remainder lowercase italics (e.g., Tyr).

Abstract

1. Melanocytes represent a relatively small subpopulation of cells, yet they are exclusively responsible for producing the melanin that accounts for virtually all visible pigmentation in the skin, hair, and eyes. Normal pigmentation requires a number of critical steps during development and a large number of genes have been shown to participate in those processes either directly or indirectly. Mutations in many of these genes produce clinical conditions of hypopigmentation, such as albinism and piebaldism.

2. Melanocytes in the skin interact with other types of cells either directly, as in the transfer of melanin granules to keratinocytes, or indirectly, as in the response to factors produced by other cells that influence the proliferation and/or pigmentation of melanocytes. Factors that regulate such melanocyte functions include environmental factors such as ultraviolet light, hormones, growth factors, cytokines, and a number of other modulators present in the milieu of the skin.

3. Tyrosinase is the critical enzyme to melanin production by virtue of its catalytic function in the hydroxylation of tyrosine, the rate-limiting reaction in the melanin biosynthetic pathway. However, there are a number of post-tyrosinase factors and enzymes that regulate the quality and quantity of melanins produced, and presumably their functional characteristics as well; included in that list are melanogenic inhibitors and other melanogenic enzymes that can modify the chemical and physical properties of melanins.

4. Two distinct types of melanins can be produced in melanocytes; these are termed eumelanins, which are black and/or brown, and pheomelanins, which are yellow and/or red. The chemical and physical characteristics, such as ultraviolet absorption, color, and solubility, of the two types of melanins are significantly different, although very little is known at present about determinants that modulate pheomelanogenesis within melanocytes.

5. The tyrosinase gene family currently contains three members: tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1, also known as TRP1 and gp75), and tyrosinase-related protein 2 (dopachrome tautomerase, TRP2, Tyrp2 (DCT), also known as TRP2, TYRP2, and Tyrp2). All three genes encode proteins with similar amino acid sequences but bind different divalent metal cations, which provides them with their distinct catalytic properties. The protein products of these three loci are thought to be involved in the multicomponent melanogenic complex in the melanosome.

6. The tyrosinase locus (TYR) has been mapped to chromosome 11q14-21; the gene is more than 65 kb in length and has 5 exons. It is the human ortholog of the murine albino locus. The TYRP1 locus (orthologous to the murine brown locus) has been mapped to chromosome 9p23; TYRP1 has been shown to be important in stabilizing tyrosinase activities in human and murine melanosomes, and in mice, Tyrp1 functions as a DHICA oxidase. The DCT locus (orthologous to the murine slaty locus) has been mapped to chromosome 13q31-32, and functions as DOPAchrome tautomerase in humans and in mice.

7. The P gene, the human ortholog of the murine pink-eyed dilution gene, has been mapped to chromosome 15q11-12. The product of this gene is localized to the melanosomal membrane, where it is thought to function in ion transport to maintain an acidic pH in the melanosome. The Pmel17 gene, the human ortholog of the murine silver gene, is involved in premature graying in mice; this locus is thought to function as a melanosomal structural matrix protein important to the polymerization of melanin. The melanocyte stimulating hormone receptor (MC1R) gene, the POMC gene and the agouti gene regulate whether black/brown eumelanin or red/yellow pheomelanin is produced.

8. The human KIT gene, which codes for a mast/stem cell growth factor, has been mapped to chromosome 4q11-13; mutations in the KIT gene are responsible for piebaldism. The PAX3 gene has been mapped to chromosome 2q35; mutations of the PAX3 and MITF genes are responsible for Waardenburg syndrome.

9. Albinism represents a group of inherited abnormalities that present with congenital hypopigmentation that can involve the skin, hair, and eyes (oculocutaneous albinism [OCA]) or can be limited primarily to the eyes (ocular albinism (OA). The definition of albinism includes specific changes in the optic system, including reduced retinal pigment with foveal hypoplasia, and misrouting of the optic fibers at the chiasm. These features must be present to make a diagnosis of albinism. Other common features include nystagmus, strabismus, and translucent irides.

10. OCA and OA are defined by the locus involved. OCA is autosomal recessive in inheritance; rare families with autosomal dominant OCA have been incompletely reported. OA is X-linked.

11. OCA1 is produced by mutations of the tyrosinase gene, and is separated into two subtypes related to the amount and the type of residual enzyme activity. Mutant alleles associated with no tyrosinase activity produce OCA1A (the classic tyrosinase-negative OCA). Mutant alleles associated with some residual activity produce OCA1B with a broad phenotypic range. Many mutations of the tyrosinase gene have been identified in OCA1, and most affected individuals are compound heterozygotes.

12. OCA2 is produced by mutations of the human P gene. The phenotypic variability in pigmentation is broad. A distinct tyrosinase-positive OCA phenotype is seen in African and African-American individuals. “Brown OCA” also results from mutations of the P gene. The hypopigmentation in Prader-Willi syndrome and Angelman syndrome is also related to the P gene, but the mechanism is unknown.

13. OCA3 (Rufous OCA) is produced by mutation of the TYRP1 gene. This type of albinism has been reported in African and African-American individuals, but clinical descriptions in other populations are not available.

14. Hermansky-Pudlak syndrome (HPS) (MIM 203300) is an infrequent autosomal recessive syndrome that presents with OCA, a mild bleeding diathesis, and a ceroid storage disease. Platelets lack dense bodies. Pulmonary fibrosis and granulomatous colitis occurs and can be severe. The HPS1 gene responsible for most HPS in Puerto Rico maps to 10q24. Chediak-Higashi syndrome (CHS) presents with hypopigmentation associated with an increased susceptibility to bacterial infections. Several types of cells, including melanocytes, contain giant granules, indicating a basic abnormality in membrane formation. The CHS1 gene maps to 1q43.

15. Ocular albinism (OA1) is produced by the OA1 gene on Xp22. Cutaneous pigment appears normal in OA1, but cutaneous and ocular melanocytes contain giant melanosomes. Heterozygous females often have retinal and iris pigment changes from mosaicism from X-inactivation.

16. Proper evaluation and management of individuals with albinism includes correct diagnosis, counseling, skin care, and ophthalmologic care.

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