A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair.
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OBJECTIVES: The goal of this study was to analyze the genetic disorder of a family with cardiomyopathy, skin disorder, and woolly hair. BACKGROUND: Arrhythmogenic right ventricular dysplasia (ARVD) is a heart muscle disorder causing arrhythmia and sudden cardiac death. We report a patient with familial autosomal recessive ARVD, woolly hair, and a pemphigous-like skin disorder with a new mutation in the desmoplakin gene. METHODS: Genomic deoxyribonucleic acid was extracted from the patient's blood and 12 first- and second-degree family members, and was amplified by polymerase chain reaction. Linkage analysis with polymorphic microsatellites was performed for 11 genes that code for structural desmosomal proteins. The genetic locus of the disease in this family was mapped to the chromosomal region 6p24 that contains the desmoplakin gene. Exons of the desmoplakin gene were analyzed by single-strand conformational polymorphism and direct sequencing. Confirmation of the mutation was carried out by restriction enzyme analysis. RESULTS: We identified in the patient a homozygous missense mutation in exon 24 of the desmoplakin gene, leading to a Gly2375Arg substitution in the C-terminal of the protein where the binding site to intermediate filaments is located. Eight of 12 family members without hair or skin abnormalities were heterozygous for this mutation. The remaining 4, as well as 90 unrelated healthy control individuals of the same ethnic origin, were homozygous for the normal allele. CONCLUSIONS: We have described a new mutation in the desmoplakin gene that causes familial ARVD. These findings suggest that desmosomal proteins play an important role in the integrity and function of the myocardium. Dysfunction of these proteins can lead to the development of cardiomyopathies and arrhythmias. (+info)
Morphological approach to hair disorders.
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The Workshop on the morphological approach to hair disorders brought together a group of clinicians involved in hair biology research. Six speakers spoke on a range of topics that can be grouped broadly into a central theme. It summarizes the evolution of medical research. The section by Tosti and coworkers describes a patient with a new unique syndrome. The section by Ferrando and colleagues provides a framework in which patients with rare hair disorders can be classified. The section by Whiting tries to define the normal anatomy of the hair follicle and both horizontal and vertical sections. It is only when normal anatomy has been absolutely defined that pathological deviations can be recognized. The section by Sinclair and coworkers attempts to estimate the reliability of histological diagnosis so that its true value of pathology can be recognized. The section by Zlotogorski and coworkers shows how accurate clinical and histological definition of disease acts as the cornerstone for gene discovery techniques. Once a causative mutation is found and a gene product identified, then the biological consequences of the altered protein product can be studied and the impact of the abnormal molecular function on hair biology can be understood. It is hoped that improved understanding of hair disease will then lead to useful therapeutic interventions. The final section by Leroy and Van Neste highlights the difficulties of evaluating therapeutic interventions in hair loss disease and proposes a new technique. (+info)
Differential expression of cyclin D1 in the human hair follicle.
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The proliferation of keratinocytes in the hair follicle varies from slowly cycling, intermittently proliferating stem cells in the bulge to rapidly proliferating, transient cells in the bulb. To better understand the biological differences between these two compartments, we sought to identify differentially expressed genes using cDNA macroarray analysis. Cyclin D1 was one of 13 genes increased in the bulge compared to the bulb, and its differential expression was corroborated by quantitative real-time polymerase chain reaction (PCR) on the original samples. Using immunohistochemical staining, laser-capture microdissection (LCM) and quantitative real-time PCR, we localized cyclin D1 to the suprabasal cells of the telogen bulge and anagen outer root sheath (ORS). Surprisingly, cyclin D1, D2, and D3 were not detectable by immunohistochemistry in the rapidly proliferating hair-producing cells of the anagen bulb (matrix cells), while these cells were strongly positive for Ki-67 and retinoblastoma protein. In contrast, pilomatricoma, a tumor thought to be derived from matrix cells, was positive for cyclin D1, D2, and D3. Our results suggest that cyclin D1 may mediate the proliferation of stem cells in the bulge to more differentiated transient amplifying cells in the suprabasal ORS. In contrast, non-cyclin D1-proteins appear to control cell division of the highly proliferative bulb matrix cells. This non-cyclin D1-mediated proliferation may provide a protective mechanism against tumorigenesis, which is overridden in pilomatricomas. Our data also demonstrate that the combination of DNA macroarray, LCM and quantitative real-time PCR is a powerful approach for the study of gene expression in defined cell populations with limited starting material. (+info)
Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients.
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Cartilage-hair hypoplasia (CHH) is an autosomal recessive form of metaphyseal chondrodysplasia characterised by short limbed short stature, hypoplastic hair growth, and impaired cell mediated immunity and erythrocyte production. The syndrome is exceptionally prevalent among the Finns and among the Old Order Amish in the United States; sporadic cases have been reported from other countries. An epidemiological and genetic study of CHH in Finland showed 107 patients, 46 males and 61 females, in 85 families. Eighteen of them had died, seven before the age of 1 year. The living patients ranged in age from 1 to 51 years, median 21 years. The incidence was estimated to be 1:23,000 live births. Consanguinity was found in two families and interfamilial relationships in 20 families. Geographical distribution of the birth places of the patients and their great grandparents showed accumulation in a small area in western Finland and regional clusters were seen in other parts of the country as well. The result of the segregation analysis was in accordance with recessive inheritance with reduced penetrance. (+info)
beta-Catenin is expressed aberrantly in tumors expressing shadow cells. Pilomatricoma, craniopharyngioma, and calcifying odontogenic cyst.
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We studied the beta-catenin immunohistochemical profile in tumors expressing shadow cells: pilomatricoma, 10 cases; calcifying odontogenic cyst, 6 cases; and craniopharyngioma, 9 cases. There was strong membranous, cytoplasmic, and nuclear staining of the immature basaloid cells in all of these tumors. Shadow cells were negative in all tumors. It has been documented that rising levels of free beta-catenin drive the formation of complexes with T-cell factor/lymphoid enhancer factor (TCF-Lef) and up-regulate the wingless-Wnt cell-cell signals. The end result is an abnormality of beta-catenin degradation and, thus, a buildup of free beta-catenin in the cytoplasm and/or nucleus, resulting in the stimulation of cellular proliferation and/or inhibition of cell death. beta-Catenin seems to have an important role in the oncogenesis of these tumors. The similar pattern of keratinization in these tumors and the similar pattern of beta-catenin immunoreactivity in the cytoplasm and the nucleus are important findings. It seems that the activation of a common cellular pathway, namely Wnt-beta-catenin-TCF-Lef, has a role in the pathogenesis of these tumors. The latter could be related to their shared method of keratinization or shared dysfunction of the cellular adhesion complex leading to tumorigenesis. (+info)
Differential repair of the two major UV-induced photolesions in trichothiodystrophy fibroblasts.
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Defects in nucleotide excision repair have been shown to be associated with the photosensitive form of the disorder trichothiodystrophy (TTD). Most repair-deficient TTD patients are mutated in the XPD gene, a subunit of the transcription factor TFIIH. Knowledge of the kinetics and efficiency of repair of the two major UV-induced photolesions in TTD is critical to understand the role of unrepaired lesions in the process of carcinogenesis and explain the absence of enhanced skin cancer incidence in TTD patients contrarily to the xeroderma pigmentosum D patients. In this study, we used different approaches to quantify repair of UV-induced cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP) at the gene and the genome overall level. In cells of two TTD patients, repair of CPD and 6-4PP was reduced compared with normal human cells, but the reduction was more severe in confluent cells than in exponentially growing cells. Moreover, the impairment of repair was more drastic for CPD than 6-4PP. Most notably, exponentially growing TTD cells displayed complete repair 6-4PP over a broad dose range, albeit at a reduced rate compared with normal cells. Strand-specific analysis of CPD repair in a transcriptional active gene revealed that TTD cells were capable to perform transcription-coupled repair. Taken together, the data suggest that efficient repair of 6-4PP in dividing TTD cells in concert with transcription-coupled repair might account for the absence of increased skin carcinogenesis in TTD patients. (+info)
Trichothiodystrophy fibroblasts are deficient in the repair of ultraviolet-induced cyclobutane pyrimidine dimers and (6-4)photoproducts.
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A photosensitive form of trichothiodystrophy (TTD) results from mutations in the same XPD gene as the DNA-repair-deficient genetic disorder xeroderma pigmentosum group D (XP-D). Nevertheless, unlike XP, no increase in skin cancers appears in patients with TTD. Although the ability to repair ultraviolet (UV)-induced DNA damage has been examined to explain their cancer-free phenotype, the information accumulated to date is contradictory. In this study, we determined the repair kinetics of cyclobutane pyrimidine dimers (CPD) and (6-4)photoproducts (6-4PP) in three TTD cell strains using an enzyme-linked immunosorbent assay. We found that all three TTD cell strains are deficient in the repair of CPD and of 6-4PP. UV sensitivity correlated well with the severity of repair defects. Moreover, accumulation of repair proteins (XPB and proliferating cell nuclear antigen) at localized DNA damage sites, detected using micropore UV irradiation combined with fluorescent antibody labeling, reflected their DNA repair activity. Importantly, mutations of the XPD gene affected both the recruitment of the TFIIH complex to DNA damage sites and the TFIIH expression. Our results suggest that there is no major difference in the repair defect between TTD and XP-D and that the cancer-free phenotype in TTD is unrelated to a DNA repair defect. (+info)
Pilomatricoma of the auricular region: case report.
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Pilomatricomas are relatively rare tumors of ectodermal origin from the outer root sheath cell of the hair follicle. They are usually asymptomatic, solitary, firm or hard, freely mobile, dermal or subcutaneous nodules. The purpose of this article is to present a case that illustrates the diagnostic difficulty encountered by oral surgeons and pathologists and to review the literature regarding pilomatricomas of the auricular region. (+info)