Faculty Bibliography

The platinum mutation at the C (albino) locus in the mouse is a potential model for oculocutaneous albinism in humans other than type IA (tyrosinase-negative) albinism. Although tissues from mice homozygous for the mutation display substantial tyrosinase activity, cutaneous and ocular pigmentation is severely restricted in affected animals. Using specific antipeptide antisera, we demonstrate that ocular extracts from wild-type mice contain two isoforms of tyrosinase bearing either the amino-terminal PEP5 epitope or the carboxy-terminal PEP7 epitope. The latter isoform participates in a high-molecular-weight complex detectable on sucrose density gradients. In platinum mice, antiserum to the PEP7 epitope fails to recognize any protein species, and the high-molecular-weight form of tyrosinase is not detectable. Our results support a key role for this high-molecular-weight complex in melanogenesis, and suggest that mutations that interfere with the ability of tyrosinase to participate in a multimeric complex may be a cause of oculocutaneous albinism in people

We cared for an infant girl with the clinical constellation of supraumbilical midabdominal raphe, sternal atresia, and cutaneous facial and upper trunk hemangioma. This is the first report of this clinical association in the dermatologic literature. The vascular component of the disorder responded to flashlamp-pumped pulsed dye laser therapy and to systemic interferon alfa-2a (Roferon-A)

BACKGROUND: Kaposi's sarcoma (KS) is commonly associated with the acquired immunodeficiency syndrome (AIDS) in adults. Little is known regarding its occurrence in children. OBJECTIVE: Our purpose was to report the clinical and epidemiologic characteristics of KS in three Romanian children with AIDS and to compare them with previously reported AIDS-associated KS in children. METHODS: This was a clinicopathologic study and computer-based literature review. RESULTS: All three Romanian children had skin involvement; two had involvement of lymph nodes and internal organs. All had acquired human immunodeficiency virus (HIV) infection postnatally. Including these children, 33 cases of AIDS-associated KS in children have been reported. Thirteen of 30 evaluable patients had acquired HIV infection postnatally; nine of these children (69%) had cutaneous involvement by KS. A perinatal route of transmission was present in the remaining 17 cases; only two of these children (12%) with KS had cutaneous involvement. No case was noted in which intravenous drug use was the sole parental HIV risk factor. CONCLUSION: The data support the contention that KS is caused by a second infectious agent prevalent only in certain HIV-infected populations. Children of parents in high-risk groups for KS and children who acquire HIV via contaminated blood or blood products are at highest risk for KS. The route of acquisition of HIV infection may also be associated with different clinical manifestations of KS in children

Coated vesicles play a critical role in the process of melanogenesis. Antisera raised against a coated vesicle fraction from mouse melanoma cells recognize two major glycoprotein antigens, band I (47-55 kd) and band II (90-120 kd). We demonstrate that band II is lysosome-associated membrane protein 1 (LAMP-1) by the following criteria: 1) the molecular weight and abundance of LAMP-1 varies among tissues but is always identical to that of band II; 2) band II and LAMP-1 co-migrate in sucrose gradient sedimentation studies; 3) immunodepletion of cell extracts with antivesicle serum removes all LAMP-1; and 4) intact organelles immunoisolated with antivesicle serum contain band II and LAMP-1. Our results further confirm the long-suspected relationship between melanosomes and the lysosomal lineage of organelles

Are tyrosinase, encoded at the albino locus, and tyrosinase-related protein-1 (TRP-1), encoded at the brown locus, similarly distributed in melanocytes? We determined the subcellular distribution of tyrosinase and TRP-1 using density fractionation of postnuclear supernatants from mouse melanoma cells of defined genotype followed by immunoblotting with specific antipeptide sera. In highly melanized cells, the majority of tyrosinase cosedimented on Percoll density gradients with visible melanin and with the peak of DOPA incorporation, confirming its presence predominantly in stage III-IV melanosomes. In contrast, the distribution of TRP-1 was limited to a less-dense melanosomal compartment, devoid of melanin. In amelanotic or minimally melanized cells, the majority of tyrosinase shifted into these lighter peaks. To explore a suspected relationship between lysosomes and melanosomes, we analyzed the distribution of lysosome-associated membrane protein-1 (LAMP-1). An overlap in the distribution of LAMP-1 and TRP-1 was demonstrated by immunomicroscopy and confirmed by immunoisolation. LAMP-1 was not present in the dense, melanin-rich melanosomal peak on gradient analysis. TRP-1 from melanoma cells homozygous for the brown mutation is not fully glycosylated, is more rapidly degraded, and is restricted in its distribution compared to its wild-type counterpart. In these mutant cells, all melanosomal compartments contain LAMP-1. Our results demonstrate that in wild-type cells the majority of tyrosinase eventually localizes to stage III-IV melanosomes. TRP-1 is limited to a less dense melanosomal compartment that is also LAMP-1 positive. The existence of this compartment suggests that it may represent a common step in the biogenesis of melanosomes and lysosomes

When human skin is exposed to ultraviolet (UV) light, a highly complex cascade of events ensues that culminates, among other things, in increased skin melanin content. From analyses at the tissue and cellular level, it has been shown that following exposure to UV light there is an increase in the number of active melanocytes in the basal layer of the epidermis, and individual melanocytes are stimulated to produce more melanin. In addition, the rate of transfer of melanosomes from melanocytes to keratinocytes is apparently increased, although the role of UV light in this process remains to be demonstrated. Recent biochemical evidence is reviewed on factors that regulate these processes. A plausible explanation for the effects of UV on pigmentation is that there are mechanisms in the skin for the orderly, regulated reception of UV signals that are then transduced to initiate the cascade. The signals involve both melanocytes and keratinocytes, and available evidence supports a model in which melanotropins and their receptors play a central role in the process