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Melanoma is the deadliest form of skin cancer and presents a significant health care burden in many countries. In addition to ultraviolet radiation in sunlight, the main causal factor for melanoma, genetic factors also play an important role in melanoma susceptibility. Although genome-wide association studies have identified many single nucleotide polymorphisms associated with melanoma, little is known about the proportion of disease risk attributable to these loci and their distribution throughout the genome. Here, we investigated the genetic architecture of melanoma in 1,888 cases and 990 controls of European non-Hispanic ancestry. We estimated the overall narrow-sense heritability of melanoma to be 0.18 (P < 0.03), indicating that genetics contributes significantly to the risk of sporadically-occurring melanoma. We then demonstrated that only a small proportion of this risk is attributable to known risk variants, suggesting that much remains unknown of the role of genetics in melanoma. To investigate further the genetic architecture of melanoma, we partitioned the heritability by chromosome, minor allele frequency, and functional annotations. We showed that common genetic variation contributes significantly to melanoma risk, with a risk model defined by a handful of genomic regions rather than many risk loci distributed throughout the genome. We also demonstrated that variants affecting gene expression in skin account for a significant proportion of the heritability, and are enriched among melanoma risk loci. Finally, by incorporating skin color into our analyses, we observed both a shift in significance for melanoma-associated loci and an enrichment of expression quantitative trait loci among melanoma susceptibility variants. These findings suggest that skin color may be an important modifier of melanoma risk. We speculate that incorporating skin color and other non-genetic factors into genetic studies may allow for an improved understanding of melanoma susceptibility and guide future investigations to identify melanoma risk genes.
Determining the mechanism of gene function is greatly enhanced using conditional mutagenesis. However, generating engineered conditional alleles is inefficient and has only been widely used in mice. Importantly, multiplex conditional mutagenesis requires extensive breeding. Here we demonstrate a system for one-generation multiplex conditional mutagenesis in zebrafish (Danio rerio) using transgenic expression of both cas9 and multiple single guide RNAs (sgRNAs). We describe five distinct zebrafish U6 promoters for sgRNA expression and demonstrate efficient multiplex biallelic inactivation of tyrosinase and insulin receptor a and b, resulting in defects in pigmentation and glucose homeostasis. Furthermore, we demonstrate temporal and tissue-specific mutagenesis using transgenic expression of Cas9. Heat-shock-inducible expression of cas9 allows temporal control of tyr mutagenesis. Liver-specific expression of cas9 disrupts insulin receptor a and b, causing fasting hypoglycemia and postprandial hyperglycemia. We also show that delivery of sgRNAs targeting ascl1a into the eye leads to impaired damage-induced photoreceptor regeneration. Our findings suggest that CRISPR/Cas9-based conditional mutagenesis in zebrafish is not only feasible but rapid and straightforward.
Copyright © 2015 by the Genetics Society of America.
HSCT can be curative for many PID. Little is known about the outcome of HSCT for patients with PID in the developing countries. We retrospectively reviewed all children with PID who received HSCT at KHCC in Jordan between August 2003 and October 2011. Twenty-eight patients were identified. The median age was 16 months (3 months-17 yr). Patients' diagnoses were SCID (n = 16), CHS (n = 3), HLH (n = 3), WAS (n = 2), Griscelli syndrome (n = 1), ALPS (n = 1), Omenn's syndrome (n = 1), and DiGeorge syndrome (n = 1). Seventeen patients received HLA-matched related HSCT, eight received maternal un-manipulated haploidentical HSCT, and three received unrelated cord blood transplantation. Nine patients (32%) developed BCGosis secondary to reactivation of pretransplant vaccination. Three died while still receiving anti-tuberculosis drugs, one still on treatment, and all others have recovered. Six patients had graft failure; four of them received no conditioning regimens. At a median follow up of 32 months (range 1-67), 21 patients are alive, with overall survival of 72%. We conclude that HSCT for PID patients can be performed with a good outcome in developing countries; however, delayed diagnosis or referral and BCG reactivation are unique challenges.
© 2013 John Wiley & Sons A/S.
The objective of this work is to report on a series of five patients with adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia (ALSP). ALSP is a rare adult-onset leukodystrophy, which encompasses hereditary diffuse leukoencephalopathy with axonal spheroids and pigmentary orthochromatic leukodystrophy. This was a retrospective chart review and literature review. Five previously healthy women presented with a rapidly progressive neurological disorder at ages 39, 37, 40, 30, and 47, respectively. All five individuals were initially diagnosed as suffering from multiple sclerosis. The clinical courses of the five patients were dominated by progressive spastic quadriparesis (patient 5, newly diagnosed, has paraparesis at this time) and dementia. Brain magnetic resonance imaging (MRI) showed diffuse cerebral atrophy, corpus callosal atrophy, and diffuse T2 hyperintensities in the subcortical and periventricular white matter with no gadolinium enhancing lesions. Three patients showed involvement of pyramidal tracts from motor cortex to the brainstem. Cerebrospinal fluid was normal in all cases. Diagnosis of ALSP was established by biopsy (two cases) and autopsy (two cases). Histopathology showed the presence of neuroaxonal spheroids in all four cases and pigmented glia in three. In the fifth case, diagnosis was established by genetic analysis alone that showed a disease-causing mutation in the colony-stimulating factor 1 receptor (CSF1R) gene. Genetic analysis was done in three patients with available DNA, and identified the disease-causing mutation in all three, including a novel mutation F828S. ALSP may be suspected in adults with rapid to subacute progression of neurological disease when (1) MRI shows corpus callosal atrophy on a background of generalized brain atrophy and diffuse white matter disease without postcontrast enhancement, (2) CSF studies are normal, and (3) studies for systemic inflammatory diseases and specific leukodystrophies are normal. Diagnosis may be made without histopathological evidence when a disease-causing mutation is demonstrated in the CSF1R gene.
Age related Macular Degeneration (AMD) is a disease of the retina associated with aging. AMD progression in patients is characterized by drusen, pigmentation changes, and geographic atrophy, which can be seen using fundus imagery. The level of AMD is characterized by standard scaling methods, which can be somewhat subjective in practice. In this work we propose a statistical image processing approach to segment drusen with the ultimate goal of characterizing the AMD progression in a data set of longitudinal images. The method characterizes retinal structures with a statistical model of the colors in the retina image. When comparing the segmentation results of the method between longitudinal images with known AMD progression and those without, the method detects progression in our longitudinal data set with an area under the receiver operating characteristics curve of 0.99.
Background adaptation is used by teleosts as one of a variety of camouflage mechanisms for avoidance of predation. Background adaptation is known to involve light sensing by the retina and subsequent regulation of melanophore dispersion or contraction in melanocytes, mediated by α-melanocyte-stimulating hormone and melanin-concentrating hormone, respectively. Here, we demonstrate that an agouti gene unique to teleosts, agrp2, is specifically expressed in the pineal and is required for up-regulation of hypothalamic pmch and pmchl mRNA and melanosome contraction in dermal melanocytes in response to a white background. floating head, a mutant with defective pineal development, exhibits defective up-regulation of mch mRNAs by white background, whereas nrc, a blind mutant, exhibits a normal response. These studies identify a role for the pineal in background adaptation in teleosts, a unique physiological function for the agouti family of proteins, and define a neuroendocrine axis by which environmental background regulates pigmentation.
PURPOSE OF REVIEW - The yellow nail syndrome (YNS) is a rare disorder of unknown cause characterized by the triad of yellow and thickened nails, lymphedema and respiratory manifestations. We review the current state of knowledge, particularly regarding the diagnosis and management of this disorder.
RECENT FINDINGS - Available data suggest acquired lymphatic dysfunction to be the predominant mechanism underlying the clinical manifestations of YNS. The clinical features are variable among individuals diagnosed to have this disorder, and these features can vary over time. Although many disorders have been reported to be associated with YNS, there is no consistent theme in these associations. Longevity of patients with YNS is modestly reduced when compared with a control population. There is no specific treatment for YNS, but most patients can be managed with supportive measures aimed at ameliorating various clinical manifestations.
SUMMARY - The pathogenesis of YNS remains poorly defined. The diagnosis is established on the basis of characteristic clinical features including abnormal nails, lymphedema and respiratory manifestations. The clinical course is generally benign, and current treatment aims to control the various clinical manifestations of this obscure disease process.
The zebrafish mutation mother superior (mosm188) leads to a depletion of neural crest (NC) derivatives including the craniofacial cartilage skeleton, the peripheral nervous system (sympathetic neurons, dorsal root ganglia, enteric neurons), and pigment cells. The loss of derivatives is preceded by a reduction in NC-expressed transcription factors, snail1b, sox9b, sox10, and a specific loss of foxd3 expression in NC progenitor cells. We employed genetic linkage analysis and physical mapping to place the mosm188 mutation on zebrafish chromosome 6 in the vicinity of the foxd3 gene. Furthermore, we found that mosm188 does not complement the sym1/foxd3 mutation, indicating that mosm188 resides within the foxd3 locus. Injection of PAC clones containing the foxd3 gene into mosm188 embryos restored foxd3 expression in NC progenitors and suppressed the mosm188 phenotype. However, sequencing the foxd3 transcribed area in mosm188 embryos did not reveal nucleotide changes segregating with the mosm188 phenotype, implying that the mutation most likely resides outside the foxd3-coding region. Based on these findings, we propose that the mosm188 mutation perturbs a NC-specific foxd3 regulatory element. Further analysis of mosm188 mutants and foxd3 morphants revealed that NC cells are initially formed, suggesting that foxd3 function is required to maintain the pool of NC progenitors.
Copyright (c) 2006 Wiley-Liss, Inc.
PURPOSE - To evaluate the incidence of and risk factors for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in survivors of hematopoietic cell transplantation (HCT).
PATIENTS AND METHODS - The impact of patient-, disease-, treatment-, and toxicity-related factors on risk of BCC and SCC was determined in a retrospective cohort study of 4,810 patients who received allogeneic HCT and who survived for at least 100 days.
RESULTS - Among allogeneic HCT recipients, 237 developed at least one skin or mucosal cancer (BCC, n = 158; SCC, n = 95). Twenty-year cumulative incidences of BCC and SCC were 6.5% and 3.4%, respectively. Total-body irradiation was a significant risk factor for BCC (P = .003), most strongly among patients younger than 18 years old at HCT (P = .02, interaction). Light-skinned patients had an increased risk of BCC (P = .01). Acute graft-versus-host disease (GVHD) increased the risk of SCC (P = .02), whereas chronic GVHD increased the risk of both BCC (P = .01) and SCC (P < .001).
CONCLUSION - This analysis suggests that immutable factors, such as age and complexion, have a significant impact on BCC and SCC. However, specific treatment (radiotherapy) and transplantation complications (GVHD) may modify that risk. These additional risk factors suggest the contribution of immunologic mechanism DNA and tissue repair in the development of BCC and SCC. We confirm previous reports that exposure to ionizing radiation increases the risk of BCC but not SCC. Survivors of HCT should be monitored for the development of BCC and SCC and use preventive strategies.