The mouse pink-eyed dilution (p) locus on chromosome 7 is associated with defects of skin, eye and coat pigmentation. Mutations at p cause a reduction of eumelanin (black-brown) pigment and altered morphology of black pigment granules (eumelanosomes), but have little effect on pheomelanin (yellow-red) pigment. We show here that the human complementary DNA DN10, linked to the p locus in mice, identifies the human homologue (P) of the mouse p gene, and appears to encode an integral membrane transporter protein. The expression pattern of this gene in various p mutant mice correlates with the pigmentation phenotype; moreover, an abnormally sized messenger RNA is detected in one mutant, p(un), which reverts to the normal size in p(un) revertants. The human P gene corresponds to the D15S12 locus within the chromosome segment 15q11-q13, which is typically deleted in patients with Prader-Willi and Angelman syndrome (see ref. 5 for review). These disorders are phenotypically distinct, depending on the parent of origin of the deleted chromosome, but both syndromes are often associated with hypopigmentation of the skin, hair and eyes (see ref. 8 for review), and deletion of the P gene may be responsible for this hypopigmentation. In addition, we report a mutation in both copies of the human P gene in one case of tyrosinase-positive (type II) oculocutaneous albinism, recently linked to 15q11-q13 (ref. 9).

Bacterial LPS (endotoxin) causes profound physiologic effects in humans and animals. These include fever, shock, and induction of the acute-phase response (1). The cell type primarily responsible for these effects is the macrophage which synthesizes large amounts of IL-1 and cachectin/tumor necrosis factor (TNF) in response to LPS (2, 3) . It is assumed that the high sensitivity to LPS derives from receptors for LPS on the macrophages. Because LPS is located on the outer leaflet of the bacterial outer membrane, we hypothesized that receptors for LPS might mediate the binding of bacteria to macrophages previously observed by several investigators (4-6). We report here that macrophages bind Escherichia coli by recognizing LPS.We have also characterized the receptors responsible for the recognition of E. coli . It is known that human macrophages express three structurally homologous receptors, CR3, lymphocyte function-associated antigen (LFA-1),' and p150,95 . Each of these surface glycoproteins consists of an a,#, dimer composed of a 150-190-kD a chain and a 95-kD 0 chain. The /3 chain is identical in each of the three proteins, but the a chains of CR3, LFA-1, and p150,95 are structurally and antigenically distinct (7,8) . Here we show that each of these dimers can promote the binding of E. coli to human macrophages.

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Polymorphonuclear leukocytes (PMN) from three patients deficient in the CD18 family of receptors (LFA-1, CR3, and p150,95) exhibited an inability to bind erythrocytes coated with C3bi or bacterial LPS. These observations confirm that the CD18 family, and CR3 in particular, can bind the structurally dissimilar molecules C3bi and LPS. Further studies showed that LPS and C3bi bind to CR3 at distinct sites. mAb OKM10 against CR3 blocked binding of C3bi to PMN but did not block the binding of LPS. In contrast, mAb 904, directed against a different epitope on CR3, blocked binding of LPS to PMN but not binding of C3bi, thus suggesting that different regions of CR3 were involved in binding these two ligands. In addition, synthetic peptides based on the sequence in C3bi recognized by CR3 competitively blocked the binding of C3bi to CR3 but did not block the binding of LPS. Rather, occupation of the peptide binding site on CR3 by the synthetic peptides enhanced binding of LPS. These results indicate that CR3 has two distinct binding sites, one that recognizes ligands composed of protein and a second that recognizes LPS.