An L1 element intronic insertion in the black-eyed white (Mitf[mi-bw]) gene: the loss of a single Mitf isoform responsible for the pigmentary defect and inner ear deafness.
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Waardenburg syndrome type 2 (WS2) is an autosomal dominant disorder characterized by a combination of pigmentary and auditory abnormalities. Approximately 20% of WS2 cases are associated with mutations in the gene encoding microphthalmia-associated transcription factor (MITF). MITF plays a critical role in the development of both neural-crest-derived melanocytes and optic cup-derived retinal pigmented epithelium (RPE); the loss of a functional Mitf in mice results in complete absence of all pigment cells, which in turn induces microphthalmia and inner ear deafness. The black-eyed white Mitf mi-bw homozygous mouse normally has a pigmented RPE but lacks melanocytes essential for the pigmentation of the body and hearing. We show here that Mitf mi-bw is caused by an insertion into intron 3 of a 7.2 kb novel L1 element, L1bw, which belongs to an actively retrotransposing TF subfamily. The L1bw insertion reduces the amount of mRNAs for two Mitf isoforms, Mitf-A and Mitf-H, by affecting their overall expression levels and pre-mRNA splicing patterns, while it abolishes mRNA expression of another isoform, Mitf-M, which is specifically expressed in neural-crest-derived melanocytes. The consequence of the L1 insertion in the black-eyed white Mitf mi-bw mouse is that the developmental programme for RPE cells proceeds normally, most likely because of the presence of residual, full-length Mitf-A and Mitf-H proteins, whereas the lack of Mitf-M results in loss of the melanocyte population. The results suggest that melanocyte development depends critically on a single Mitf isoform, Mitf-M, and raise the possibility that specific mutations affecting MITF-M, the human equivalent of Mitf-M, may be responsible for a subset of WS2 conditions. (+info)
A case of melanonychia caused by Exophiala dermatitidis.
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We report a case of a healthy 61-year-old woman with discoloration of the nail on her right big toe. We first treated her with topical steroid and urea under suspected diagnosis of nail eczema, but the lesion remained. In culture, black, shiny, pasty and yeast-like colonies grew repeatedly. Examination of debris from her nail showed dematiaceous spherical cells and hyphal elements. Microscopically, annelloconidia were produced at the apical ends of anellidic conidiogenous cells. This colony grew at 40C. Mitochondrial DNA restriction fragment length polymorphism was analysed in this strain and its restriction pattern confirmed the isolate to be Exophiala dermatitidis. Based on these findings, we diagnosed this nail deformity as fungal melanonychia due to Exophiala dermatitidis. This is the third reported case of this disease. (+info)
Altered gene expression in melanocytes exposed to 4-tertiary butyl phenol (4-TBP): upregulation of the A2b adenosine receptor 1.
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Exposure to phenolic agents contributes to the development of occupational vitiligo. Proposed as a causative factor for leukoderma in vivo, the para-substituted phenol 4-tertiary butyl phenol was chosen to investigate early cellular events responsible for selective disappearance of melanocytes from the epidermis of individuals sensitive to such agents. To this end, differential display of melanocyte mRNA isolated from three separate cultures was performed following a 12 h exposure of cells to 250 microM 4-tertiary butyl phenol or to vehicle alone. Fragments of cDNA representing differentially expressed messages were cloned and subsequently confirmed by reverse dot blotting. Alignment analysis revealed that the L30 ribosomal protein was upregulated by the treatment, potentially reflecting altered levels of protein synthesis in response to stress. In addition, a gene sequence upregulated following exposure to 4-tertiary butyl phenol was identified as the A2b receptor (a P1 receptor for adenosine). Differential expression of this gene was confirmed in an RNase protection assay. By reverse transcription-polymerase chain reaction, the gene was shown to be expressed in keratinocytes and fibroblasts as well. Flow cytometry confirmed differential expression in melanocytes and fibroblasts, but not in keratinocytes. Interestingly, it has been reported that P1 purinoceptor stimulation can induce apoptosis. This is in concordance with results reported elsewhere demonstrating induction of apoptosis by 4-tertiary butyl phenol in human melanocytes, as well as with morphologic changes observed in this study in cells exposed to 250 microM 4-tertiary butyl phenol for 72 h. In conclusion, differential display is useful to establish melanocyte components involved in the cellular response to phenolic agents. (+info)
Epidemic dropsy in India.
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Epidemic dropsy is a clinical state resulting from use of edible oils adulterated with Argemone mexicana oil. Sanguinarine and dehydrosanguinarine are two major toxic alkaloids of Argemone oil, which cause widespread capillary dilatation, proliferation and increased capillary permeability. Leakage of the protein-rich plasma component into the extracellular compartment leads to the formation of oedema. The haemodynamic consequences of this vascular dilatation and permeability lead to a state of relative hypovolemia with a constant stimulus for fluid and salt conservation by the kidneys. Illness begins with gastroenteric symptoms followed by cutaneous erythema and pigmentation. Respiratory symptoms such as cough, shortness of breath and orthopnoea progressing to frank right-sided congestive cardiac failure are seen. Mild to moderate anaemia, hypoproteinaemia, mild to moderate renal azotemia, retinal haemorrhages, and glaucoma are common manifestations. There is no specific therapy. Removal of the adulterated oil and symptomatic treatment of congestive cardiac failure and respiratory symptoms, along with administration of antioxidants and multivitamins, remain the mainstay of treatment. Selective cultivation of yellow mustard, strict enforcement of the Indian Food Adulteration Act, and exemplary punishment to unscrupulous traders are the main preventive measures. (+info)
Terminal osseous dysplasia with pigmentary defects maps to human chromosome Xq27.3-xqter.
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We have identified a four-generation family with 10 affected females manifesting one or more of the following features: osseous dysplasia involving the metacarpals, metatarsals, and phalanges leading to brachydactyly, camptodactyly, and other digital deformities; pigmentary defects on the face and scalp; and multiple frenula. There were no affected males. We performed X-inactivation studies on seven affected females, using a methylation assay at the androgen receptor locus; all seven demonstrated preferential inactivation of their maternal chromosomes carrying the mutation, and two unaffected females showed a random pattern. These findings indicate that this disorder is linked to the X chromosome. To map the gene for this disorder, we analyzed DNA from nine affected females and five unaffected individuals, using 40 polymorphic markers evenly distributed throughout the X chromosome. Two-point and multipoint linkage analyses using informative markers excluded most of the X chromosome and demonstrated linkage to a region on the long arm between DXS548 and Xqter. A maximum LOD score of 3.16 at recombination fraction 0 was obtained for five markers mapping to Xq27.3-Xq28. The mapping data should facilitate the identification of the molecular basis of this disorder. (+info)
An unbalanced submicroscopic translocation t(8;16)(q24.3;p13.3)pat associated with tuberous sclerosis complex, adult polycystic kidney disease, and hypomelanosis of Ito.
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We report on a familial submicroscopic translocation involving chromosomes 8 and 16. The proband of the family had a clinical picture suggestive of a large deletion in the chromosome 16p13.3 area, as he was affected with tuberous sclerosis complex (TSC) and had alpha thalassaemia trait, and his half brother, who also had TSC, may have suffered additionally from polycystic kidney disease (PKD). FISH studies provided evidence for a familial translocation t(8;16)(q24.3;p13.3) with an unbalanced form in the proband and a balanced form in the father and in a paternal aunt. The unbalanced translocation caused the index patient to be deleted for the chromosome 16p13.3-pter region, with the most proximal breakpoint described to date for terminal 16p deletions. In addition, FISH analysis showed a duplication for the distal 8q region. Since the index patient also had hypomelanosis of Ito (HI), either of the chromosomal areas involved in the translocation may be a candidate region for an HI determining gene. Furthermore, it is noteworthy that both carriers of the balanced translocation showed a nodular goitre, while the proband has hypothyroidism. (+info)
Problematic pigmented lesions: approach to diagnosis.
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A number of pigmented lesions are difficult to classify and raise the possibility of a melanoma diagnosis. Care should be exercised to exclude non-melanocytic lesions, and benign melanocytic entities, both of which can mimic melanoma histologically. In addition, the possibility of the lesion being a melanoma variant or epidermotropic metastasis should be considered. There will still be some cases that are difficult to resolve. These usually fall into one of three categories: atypical junctional melanocytic lesion versus early melanoma; naevus versus naevoid melanoma; and atypical Spitz, cellular blue, and deep penetrating naevi versus thick melanoma. These will pose problems even for experts. The atypical Spitz lesions are perhaps the most important category because they tend to be from younger individuals, the differential diagnosis is thick melanoma, and there is no single discriminating histological feature. (+info)
A quantitative evaluation of pigmented skin lesions using the L*a*b* color coordinates.
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The evaluation of pigmentary skin lesions by clinical doctors has been based on subjective and qualitative judgements. Observations have mostly relied on visual inspection, making the effects of treatment difficult to evaluate with any precision. For this reason there is a real need for an objective method to evaluate prognosis after treatment. Recent scientific measurements such as reflectance spectrophotometry and reflectance colorimetry have provided accurate quantitative color information about skin lesions, but these techniques are costly and difficult to apply in the clinical field. The purpose of this study was to develop a simple and cost-effective way of evaluating treatment results. We have developed a software program using the L*a*b* color coordinate system to quantify the effect of treatment and have successfully demonstrated its clinical usefulness. Our method compares the relative color difference between normal skin and skin lesions before and after treatment, instead of measuring the absolute color of skin lesions. The accuracy of our quantitative color analysis was confirmed by the simulated images of hemangioma and ota nevus. Clinical efficacy was also confirmed through a blind test involving 3 clinicians who were asked to grade the treatment effects of 13 cases of hemangioma and 7 cases of ota nevus. These subjective clinical grades correlated well with the treatment results obtained using the proposed color analysis system (Correlation coefficient = 0.84). (+info)