Refractory cutaneous alternariosis successfully treated with Mohs surgery and full-thickness skin grafting.
Simpson CL, Craig-Muller S, Sobanko JF, Weikert BC, Micheletti RG
Dermatologic Surgery, 42(3):426-9. DOI: 10.1097/DSS.0000000000000625
PMID: 26945322
Dynamic actin cycling through mitochondrial subpopulations locally regulates the fission-fusion balance within mitochondrial networks.
Moore AS, Wong YC, Simpson CL, Holzbaur EL
Nature Communications, 7:12886. DOI: 10.1038/ncomms12886
PMID: 27686185
View Abstract and Highlights
Mitochondria form interconnected networks that dynamically remodel in response to cellular needs. Using live-cell imaging, we investigate the role of the actin cytoskeleton in regulating mitochondrial fission and fusion. We identify cycling of actin filaments onto and off of subsets of cellular mitochondria. The association of actin filaments with mitochondrial subpopulations is transient; actin quickly disassembles, then reassembles around a distinct subpopulation, efficiently cycling through all cellular mitochondria within 14 min. The focal assembly of actin induces local, Drp1-dependent fragmentation of the mitochondrial network. On actin disassembly, fragmented mitochondria undergo rapid fusion, leading to regional recovery of the tubular mitochondrial network. Cycling requires dynamic actin polymerization and is blocked by inhibitors of both Arp2/3 and formins. We propose that cyclic assembly of actin onto mitochondria modulates the fission/fusion balance, promotes network remodelling and content mixing, and thus may serve as an essential mechanism regulating mitochondrial network homeostasis.
Photo-distributed lichenoid eruption secondary to direct anti-viral therapy for hepatitis C.
Simpson CL, McCausland D, Chu EY
Journal of Cutaneous Pathology, 42(10):769-73. DOI: 10.1001/jamapediatrics.2015.1359
PMID: 25974215
View Abstract and Highlights
Novel direct anti-viral agents are emerging as effective treatments for hepatitis C virus (HCV) and provide an alternative to the year-long standard therapy with interferon and ribavirin. However, cutaneous side effects from these new medications, including rash, pruritus and photosensitivity, are among the most commonly reported adverse events and have resulted in therapy discontinuation in some cases. Here, we report two cases of a photo-distributed lichenoid eruption that occurred within 1 month of starting anti-viral therapy with simeprevir and sofosbuvir without interferon or ribavirin. This report provides the first histologic description of the cutaneous eruption associated with direct anti-viral therapy for HCV and highlights the importance of recognizing and treating the often intolerable dermatologic side effects of these novel medications, the incidence of which is likely to increase as direct anti-viral agents may become the standard of care for HCV.
A Crusted Papule in a Premature Neonate.
Simpson CL, Boos MD, Castelo-Soccio L
JAMA Pediatrics, 169(12):1173-4. DOI: 10.1001/jamapediatrics.2015.1359
PMID: 26642112
View Abstract and Highlights
A male neonate was born at 25 weeks’ gestation by cesarean delivery because of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome in his primigravid mother, who also had systemic lupus erythematosus managed with hydroxychloroquine, aspirin, and prednisone during pregnancy. The patient’s premature birth was complicated by acute respiratory distress that necessitated intubation and necrotizing enterocolitis that required parenteral nutrition. At birth, the patient was found to be mildly anemic (hemoglobin level, 11.0 g/dL [to convert to grams per liter, multiply by 10]) and thrombocytopenic (platelet count, 120 × 103/µL [to convert to 109/L, multiply by 1]) with concomitant intraventricular hemorrhage. Although afebrile, he was treated empirically for sepsis with vancomycin hydrochloride and cefepime hydrochloride. A cerebrospinal fluid culture result was positive for Staphylococcus epidermidis, but the results of additional blood cultures were negative for organisms. On day 8 after birth, a 0.5-cm, circular, crusted papule with a surrounding rim of erythema on the left hip was noted. A punch biopsy of the lesion was performed.
Infant with a Unilateral Parotid Mass, Recurrent Otitis Media, and Macrocephaly: Plexiform Neurofibroma.
Boos MD, Simpson CL, Castelo-Soccio L
JAMA Pediatrics, 169(8):783-4. DOI: 10.1001/jamapediatrics.2015.0900
PMID: 26237456
View Abstract and Highlights
A 9-month-old boy presented with a left-sided facial mass. His perinatal history was notable for macrosomia, macrocephaly, left-sided failure on newborn hearing screen, and a congenital hypertrichotic patch of the left scalp. During the first few months, he was observed to frequently tug at his left ear while displaying apparent discomfort and sleeping difficulties. He was treated empirically with multiple antibiotics for presumed otitis media and subsequently had bilateral myringotomy tubes placed. When the left side of his face became more swollen, magnetic resonance imaging was performed at 8 months of age and revealed a left-sided parotid mass. He was referred to our institution for further evaluation.
Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation.
Harmon RM, Simpson CL, Johnson JL, Koetsier JL, Dubash AD, Najor NA, Sarig O, Sprecher E, Green KJ
Journal of Clinical Investigation, 123(4):1556-70. DOI: 10.1172/JCI65220
PMID: 23524970
View Abstract and Highlights
Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The desmosomal cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.
The calcium ATPase SERCA2 regulates desmoplakin dynamics and intercellular adhesive strength through modulation of PKCα signaling.
Hobbs RP, Amargo EV, Somasundaram A, Simpson CL, Prakriya M, Denning MF, Green KJ
FASEB Journal, 25(3):990-1001. DOI: 10.1096/fj.10-163261
PMID: 21156808
View Abstract and Highlights
Darier’s disease (DD) is an inherited autosomal-dominant skin disorder characterized histologically by loss of adhesion between keratinocytes. DD is typically caused by mutations in sarcoendoplasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2), a major regulator of intracellular Ca(2+) homeostasis in the skin. However, a defined role for SERCA2 in regulating intercellular adhesion remains poorly understood. We found that diminution of SERCA2 function by pharmacological inhibition or siRNA silencing in multiple human epidermal-derived cell lines was sufficient to disrupt desmosome assembly and weaken intercellular adhesive strength. Specifically, SERCA2-deficient cells exhibited up to a 60% reduction in border translocation of desmoplakin (DP), the desmosomal cytolinker protein necessary for intermediate filament (IF) anchorage to sites of robust cell-cell adhesion. In addition, loss of SERCA2 impaired the membrane translocation of protein kinase C α (PKCα), a known regulator of DP-IF association and desmosome assembly, to the plasma membrane by up to 70%. Exogenous activation of PKCα in SERCA2-deficient cells was sufficient to rescue the defective DP localization, desmosome assembly, and intercellular adhesive strength to levels comparable to controls. Our findings indicate that SERCA2-deficiency is sufficient to impede desmosome assembly and weaken intercellular adhesive strength via a PKCα-dependent mechanism, implicating SERCA2 as a novel regulator of PKCα signaling.
Plakoglobin rescues adhesive defects induced by ectodomain truncation of the desmosomal cadherin, desmoglein 1: Implications for exfoliative toxin-mediated skin blistering.
Simpson CL, Kojima SI, Cooper-Whitehair V, Getsios S, Green KJ
American Journal of Pathology, 177(6):2921-37. DOI: 10.2353/ajpath.2010.100397
PMID: 21075858
View Abstract and Highlights
Desmoglein 1 (Dsg1) is a desmosomal cadherin that is essential to epidermal integrity. In the blistering diseases bullous impetigo and staphylococcal scalded-skin syndrome, pathogenesis depends on cleavage of Dsg1 by a bacterial protease, exfoliative toxin A, which removes residues 1 to 381 of the Dsg1 ectodomain. However, the cellular responses to Dsg1 cleavage that precipitate keratinocyte separation to induce blister formation are unknown. Here, we show that ectodomain-deleted Dsg1 (Δ381-Dsg1) mimics the toxin-cleaved cadherin, disrupts desmosomes, and reduces the mechanical integrity of keratinocyte sheets. In addition, we demonstrate that truncated Dsg1 remains associated with its catenin partner, plakoglobin, and causes a reduction in the levels of endogenous desmosomal cadherins in a dose-dependent manner, leading us to hypothesize that plakoglobin sequestration by truncated Dsg1 destabilizes other cadherins. Accordingly, a triple-point mutant of the ectodomain-deleted cadherin, which is uncoupled from plakoglobin, does not impair adhesion, indicating that this interaction is essential to the pathogenic potential of truncated Dsg1. Moreover, we demonstrate that increasing plakoglobin levels rescues cadherin expression, desmosome organization, and functional adhesion in cells expressing Δ381-Dsg1 or treated with exfoliative toxin A. Finally, we report that histone deacetylase inhibition up-regulates desmosomal cadherins and prevents the loss of adhesion induced by Dsg1 truncation. These findings further our understanding of the mechanism of exfoliative toxin-induced pathology and suggest novel strategies to suppress blistering in bulbous impetigo and staphylococcal scalded-skin syndrome.