Faculty Bibliography

There is a continual need for compounds that effectively modulate melanin synthesis. To identify novel pigmentation modulators and their cellular targets, chemical genetic screenings were performed with triazine-based combinatorial libraries that include various linkers as intrinsic components of the small molecules in the library. The linker provides a ready means of attachment to beads, eliminating several common time-consuming downstream steps in the isolation of cellular targets for the small molecules of interest. Twelve compounds were identified as novel pigmentation modulators from various screenings performed in normal and albino murine melanocytes and zebrafish. Target identification by affinity chromatography revealed unexpected roles for prohibitin and mitochondrial F1F0-adenotriphosphatase in the regulation of mammalian pigmentation. The identification of prohibitin, a "scaffold protein", as a propigmentation effector represents a novel mechanism by which propigmentary signals are transduced. Results from our screenings provide potential active agents and targets for the medical and aesthetic treatment of disorders of pigmentation.

The ocular albinism 1 (Oa1) protein is believed to be involved in the biogenesis of melanosomes, but its cellular localization is controversial and its function is unknown. Based upon sequence homology, it has been predicted that Oa1 belongs to the G protein coupled receptor (GPCR) superfamily. We used the yeast Saccharomyces cerevisiae as a genetically amenable system to study the localization and function of Oa1. Sucrose gradient and immunofluorescence studies revealed that when expressed in yeast, Oa1 localizes to the prevacuolar compartment, the functional equivalent of the mammalian late endosome. Oa1 behaved as G protein coupled receptor in a yeast-based GPCR signalling assay. Extracts of cultured melanocytes, and, in particular, a particulate fraction from cultured melanocytes, stimulated Oa1-mediated GPCR signalling

BACKGROUND: The spectrum of clinical findings associated with PTEN tumor suppressor gene germline mutations, referred to as PTEN hamartoma-tumor syndrome (PHTS), includes Cowden and Bannayan-Riley-Ruvalcaba syndromes. Although the skin is the ectodermal structure most often affected by these autosomal dominant genodermatoses, abnormalities of neural tissues are frequently observed. OBSERVATIONS: We describe a 5-year-old boy with macrocephaly, prominent corneal nerves, and progressive development of multiple painful, dome-shaped, translucent pink to skin-colored papules on the vermilion portion of the upper lip, fingers, palms, and shins. Histologic evaluation demonstrated dermal proliferation of well-demarcated nerve bundles associated with abundant mucin and surrounded by a distinct perineural sheath, findings diagnostic of a nonencapsulated neuroma. Genetic analysis revealed a novel heterozygous germline nonsense mutation in PTEN, predicted to result in a truncated PTEN protein. To our knowledge, this represents the first report of multiple neuromas as the sole mucocutaneous manifestation of PHTS. CONCLUSIONS: This article highlights neuromas as a cutaneous sign of PHTS, drawing attention to manifestations of PHTS in neural tissues of the skin, eye, gastrointestinal tract, and brain. Along with multiple endocrine neoplasia type 2B, PHTS should be considered in the differential diagnosis of multiple mucocutaneous neuromas, particularly those involving extrafacial sites

The processing and trafficking of tyrosinase, a melanosomal protein essential for pigmentation, was investigated in a human epithelial 293 cell line that stably expresses the protein. The effects of the pink-eyed dilution (p) gene product, in which mutations result in oculocutaneous albinism type 2 (OCA2), on the processing and trafficking of tyrosinase in this cell line were studied. The majority of tyrosinase was retained in the endoplasmic reticulum-Golgi intermediate compartment and the early Golgi compartment in the 293 cells expressing the protein. Coexpression of p could partially correct the mistrafficking of tyrosinase in 293 cells. Tyrosinase was targeted to the late endosomal and lysosomal compartments after treatment of the cells with compounds that correct the tyrosinase mistrafficking in albino melanocytes, most likely through altering intracellular pH, while the substrate tyrosine had no effect on the processing of tyrosinase. Remarkably, this heterologous expression system recapitulates the defective processing and mistrafficking of tyrosinase observed in OCA2 albino melanocytes and certain amelanotic melanoma cells. Coexpression of other melanosomal proteins in this heterologous system may further aid our understanding of the details of normal and pathologic processing of melanosomal proteins

Localized autosomal recessive hypotrichosis (LAH) is a recently defined disorder characterized by fragile, short, sparse hairs on the scalp, trunk, and extremities. Mutations in desmoglein 4 (DSG4), a novel member of the desmosomal cadherin family that is expressed in the hair follicle as well as the suprabasal epidermis, have been found to underlie LAH. Thus far, the allelic series includes a recurrent intragenic deletion identified in affected Pakastani kindreds and a missense mutation detected in an Iraqi family. We report three siblings of Iraqi and Iranian origin with LAH that presented with congenital scalp erosions and monilethrix-like hairs, features that have not been previously described in this disorder. Follicular hyperkeratotic papules and marked pruritus were also prominent clinical findings. Novel compound heterozygous DSG4 mutations, including a splice-site mutation and a missense mutation that disrupts a conserved calcium-binding site in the extracellular (EC)2-EC3 interface, were found to underlie the disease in this family. These observations broaden the phenotypic and genotypic spectrum of LAH, further illustrating the consequences of DSG4 dysfunction on epidermal and hair shaft integrity

Phacomatosis pigmentokeratotica (PPK) represents a specific 'twin nevus' syndrome in which a speckled lentiginous nevus (SLN) is associated with an organoid nevus with sebaceous differentiation. A boy with a large nevus sebaceus on the left face and upper part of the trunk, a giant segmental SLN extending from the abdomen to the feet bilaterally, and right hemihypertrophy developed an embryonal rhabdomyosarcoma of the right abdominal wall at age 6 months. A variety of musculoskeletal, neurologic, and ocular anomalies have been observed in patients with PPK, reflecting the individual manifestations of both SLN and Schimmelpenning syndromes. This report adds hemihypertrophy to the spectrum of extracutaneous manifestations of PPK and, to our knowledge, represents the first observation of a rhabdomyosarcoma arising in contiguity with an SLN in a patient with PPK. The development of a rhabdomyosarcoma in our patient likely reflects both increased propensity for growth (as evidenced by the hemihypertrophy) and the pluripotent nature of neural-crest derived cells within the field defect that underlies an SLN

BACKGROUND: Atopic dermatitis (AD) is increasingly common, with a point prevalence of more than 30% in some countries, and is characterized by visible skin lesions and intense itching. OBJECTIVE: The International Study of Life with Atopic Eczema (ISOLATE) is the first large-scale study to assess the effect of AD on the lives of patients and society, how patients and caregivers manage the condition, and how well patients and caregivers currently believe that AD is controlled. METHODS: Two thousand two patients (>13 years) and caregivers of children (2-13 years) with moderate-to-severe AD randomly selected from 8 countries underwent standardized telephone interviews using questions developed in collaboration with national eczema patient groups and physicians. RESULTS: During each year, patients spend, on average, 1 of 3 days in flare. The majority of patients receive prescription topical corticosteroids to treat flares; however, 49% of respondents are concerned about using these agents. On average, patients and caregivers delay initiating treatment for 7 days after onset of a flare. Only 24% of patients and caregivers feel confident they can manage AD flares adequately. Seventy-five percent of caregivers and patients feel that being able to effectively control AD would be the single most important improvement to their or their child's quality of life. The avoidable secondary economic cost of AD is estimated at 2 billion Euro per year across the European Union. CONCLUSION: ISOLATE highlights the need to improve patients' control of AD to reduce the significant effect this condition has on the patient and society. CLINICAL IMPLICATIONS: ISOLATE shows that patients with AD are untreated for half the time they are in flare, and thus there is an urgent need for physicians to ensure that the patients are educated and confident in using medication as prescribed to gain disease control

A 7-year-old girl presented with asymptomatic bruise-like hairy nodules on her right lower leg since 8 months of age. Histopathology demonstrated an increased number of blood vessels and eccrine glands, thicker collagen bundles, and a terminal hair follicle in catagen phase. The patient was diagnosed with multiple eccrine pilar angiomatous nevi, an unusual variant of eccrine angiomatous hamartomas. The natural course of eccrine angiomatous hamartomas is typically slow growth and benign behavior. Simple excision is usually curative and is reserved for painful or cosmetically disfiguring lesions. Our patient's nevus is large and multifocal, making excision more challenging