The etiology and molecular genetics of human pigmentation disorders

Abstract

Pigmentation, defined as the placement of pigment in skin, hair, and eyes for coloration, is distinctive because the location, amount, and type of pigmentation provides a visual manifestation of genetic heterogeneity in pathways regulating the pigment-producing cells, melanocytes. The scope of this genetic heterogeneity in humans ranges from normal to pathological pigmentation phenotypes. Clinically, normal human pigmentation encompasses a variety of skin and hair color as well as punctate pigmentation such as melanocytic nevi (moles) or ephelides (freckles), while abnormal human pigmentation exhibits markedly reduced or increased pigment levels, known as hypopigmentation and hyperpigmentation, respectively. Elucidation of the molecular genetics underlying pigmentation has revealed genes important for melanocyte development and function. Furthermore, many pigmentation disorders show additional defects in cells other than melanocytes, and identification of the genetic insults in these disorders has revealed pleiotropic genes, where a single gene is required for various functions in different cell types. Thus, unravelling the genetics of easily visualized pigmentation disorders has identified molecular similarities between melanocytes and less visible cell types/tissues, arising from a common developmental origin and/or shared genetic regulatory pathways. Herein we discuss notable human pigmentation disorders and their associated genetic alterations, focusing on the fact that the developmental genetics of pigmentation abnormalities are instructive for understanding normal pathways governing development and function of melanocytes.

Figure 1

Diagrammatic representation of congenital human cutaneous pigmentation abnormalities. A) Normal skin shows individual, dendritic melanocytes located at the basal cell layer of the epidermis and in the bulb of the hair follicle. Epidermal melanocytes provide pigment to surrounding interfollicular keratinocytes, and follicular melanocytes provide pigment to hair shaft keratinocytes. B) In Waardenburg syndrome, developmental anomalies in genes crucial for pigment cell development cause regionalized absence of melanocytes, resulting in areas of hypopigmented skin and hair. C) In oculocutaneous albinism, melanocytes are retained, but they contain a genetic defect that prevents them from producing normal levels of melanin. Illustrated is OCA1A, where complete absence of pigment results from loss of function of the melanogenic enzyme TYR. Other forms of oculocutaneous albinism typically show some residual pigmentation. D) Melanocytic nevi show benign overgrowth of epidermal melanocytes that have lost their dendritic form and are organized in defined nests. E) In dermal melanocytosis, melanocytes retaining dendritic morphology are found within the dermis, in a scattered array often parallel to the skin’s surface. Their deeper, dermal location gives them a characteristic blue tint, with a superficial dermal location typical for nevus of Ito or nevus of Ota, and a deeper dermal location for Mongolian spots. F) In ephelides, normal numbers of melanocytes produce localized patches of increased melanin in surrounding keratinocytes. Formation of ephelides is directly correlated with UV irradiation levels.