The Mouse p (pink‐eyed dilution) and Human P Genes, Oculocutaneous Albinism Type 2 (OCA2), and Melanosomal pH

Abstract

Recessive mutations of the mouse p (pink-eyed dilution) gene lead to hypopigmentation of the eyes, skin, and fur. Mice lacking a functional p protein have pink eyes and light gray fur (if non-agouti) or cream-colored fur (if agouti). The human orthologue is the P protein. Humans lacking a functional P protein have oculocutaneous albinism type 2 (OCA2). Melanocytes from p-deficient mice or OCA2 individuals contain small, minimally pigmented melanosomes. The mouse and human proteins are predicted to have 12 membrane spanning domains and possess significant sequence homology to a number of membrane transport proteins, some of which are involved in the transport of anions. The p protein has been localized to the melanosome membrane. Recently, it has been shown that melanosomes from p protein-deficient melanocytes have an abnormal pH. Melanosomes in cultured melanocytes derived from wild-type mice are typically acidic, whereas melanosomes from p protein-deficient mice are non-acidic. Melanosomes and related endosome-derived organelles (i.e., lysosomes) are thought to have an adenosine triphosphate (ATP)-driven proton pump that helps to generate an acidic lumen. To compensate for the charge of these protons, anions must also be transported to the lumen of the melanosome. In light of these observations, a model of p protein function is presented in which the p protein, together with the ATP-driven proton pump, regulates the pH of the melanosome.

Inheritance of a novel mutated allele of the OCA2 gene associated with high incidence of oculocutaneous albinism in a Polynesian community

“…(Figure 4). 15 OCA2 albinism in Polynesia HC Johanson et al identified in these individuals, although they were not sequenced across all exons for this study. One Australian Caucasian with OCA was found to be a compound heterozygote for one novel apparent pathological missense mutation b.1185G4T, OCA2 p.Met395Ile and one common hypopigmentation-related allele b.1327G4A, p.Val443Ile.…”

“…Structurally, the 838 amino-acid P-protein is predicted to contain 12 transmembrane-spanning domains. The cDNA is encoded in 24 exons, 14,15 and the locus covers over 345 kb. 16 Though initially reported as an integral melanosomal protein potentially associated with transport of some molecule into the melanosome, its subcellular localization has been a subject of debate.…”

“…16 Though initially reported as an integral melanosomal protein potentially associated with transport of some molecule into the melanosome, its subcellular localization has been a subject of debate. It has been proposed to regulate melanosomal pH, 15 with an additional possible role in the processing and trafficking of melanosomal proteins. 17,18 It has recently been confirmed as localizing with mature melanosomes.…”

Pink-eyed Dilution Protein Controls the Processing of Tyrosinase

“…However, other investigators have reached opposite conclusions. Puri et al (Puri et al, 2000) proposed that the pH of melanosomes in p-null melanocytes is not acidic, whereas an acidic melanosomal environment is important for melanin synthesis (Brilliant, 2001). However, the use of tyrosinaserelated protein 1 (Tyrp1), a Tyr family protein that shares 43% amino acid sequence identity with Tyr (Vijayasaradhi et al, 1995), as a melanosomal marker in p-null melanocytes may be inappropriate because Tyrp1, like Tyr, is mislocalized in the absence of p .…”

Genotype–phenotype associations and human eye color

“…In mice and humans where the P protein is nonfunctional, albinism occurs, indicating its crucial role in pigmentation. 13,14 The gene located 11.7 kb from HERC2 requires 345 kb, but it requires only 24 exons to produce a 110 kDa protein with 838 residues. These two seemingly unrelated genes have a major effect on eye color in humans.…”