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At least 19 recordsLinked to original sources
PubMed2002

Molecular advances in genetic skin diseases.

The genes for several genetic skin diseases have been identified in recent years. This development improves diagnostic capabilities and genetic counseling, and investigators can now turn to the molecular mechanisms involved in the pathogenesis of these diseases. The identification of the causative genes has led to the generation of mouse models for some genetic skin diseases. A study of the keratin 10 deficient mouse, a model for epidermolytic hyperkeratosis, and a mouse model for Bloom syndrome are reviewed in this article. Several studies also evaluate the relation between genotype and phenotype. In this article, the clinical findings and molecular advances in tuberous sclerosis complex, neurofibromatosis type 1, Bloom syndrome, epidermolytic hyperkeratosis, X-linked ichthyosis, Netherton syndrome, and Hermansky-Pudlak syndrome are reviewed.

Genetic Therapy↗
PubMed2000

[Hope for new therapies of severe genetic skin diseases].

The skin barrier is composed of a thin horny layer, which prevents water loss and intrusion of noxious factors, and a thicker, viable layer of epidermis, which is strongly attached to the underlying dermis. Serious impairment of the skin barrier may result from genetic diseases interfering with the attachment and/or terminal differentiation of keratinocytes. In epidermolysis bullosa, defects in the anchoring proteins of epidermis cause neonatal blistering and a life-long problem with widespread skin erosions. In congenital ichthyosis, various enzyme deficiencies (transglutaminase 1, steroid sulfatase, etc) or mutations in structural proteins (cytokeratins, plakophilin, etc) cause massive hyperkeratosis and/or inflammation resulting in chronic problems with the skin barrier. Our increasing knowledge of the etiology of these diseases has already facilitated diagnosis and genetic counseling. Hopefully this knowledge will also pave the way for new remedies, including cutaneous gene therapy for the most severe conditions.

Cell Division↗
PubMed1997

Genetic skin diseases with altered aging.

Integration, homeostasis, and redundancy of function are hallmarks of important biological processes. Individual gene defects may overcome and override normal homeostatic systems and lead to dramatic, recognizable phenotypes by profoundly altering 1 or more physiological systems. Classical human geneticists interested in a monogenetic disease began at the level of altered function and struggled to determine the genomic defect of that disease. In the past 1 1/2 decades, many monogenetic defects have been identified by positional cloning, and the abnormal gene has been characterized. A challenge for current investigators is to understand how a genetic defect, identified by a DNA mutation, leads to the altered phenotype. This effort is not trivial, since there are multiple metabolic and structural consequences of a single altered gene. Further complexity results from individual genetic changes being modified by the genetic diversity of the human host. Pleiotropy refers to the phenomenon of multiple phenotypic effects of a single gene.

Aging↗
PubMed1993

Prenatal diagnosis of genetic skin disease using fetal skin biopsy samples.

BACKGROUND: Understanding normal skin development and identifying markers of genetic skin disease expressed in postnatal skin have permitted the prenatal diagnosis of many severe genodermatoses: bullous diseases, keratinization diseases, pigment cell disorders, and disorders of the epidermal appendages (ectodermal dysplasias). Samples of 16 to 22 weeks' gestation fetal skin obtained by ultrasound-guided biopsy are evaluated using morphologic, immunohistochemical, and biochemical methods. OBSERVATIONS: The 12-year experience in evaluating samples from fetuses at risk of these disorders has allowed us to establish conditions that must be met before the samples are taken and the criteria for recognizing the disorder, to recommend the site(s) for sampling, and to be mindful of pitfalls that may be encountered in interpreting the tissue structure. CONCLUSIONS: Fetal skin biopsy is an important diagnostic tool that has permitted families in which members carry the abnormal gene for one of these severe skin diseases to undertake a pregnancy knowing that the condition of the fetus can be determined. Nonetheless, the ultimate goal is phase out this procedure when linkage of more of these disorders to specific genes is understood, specific mutations are characterized, and probes are available for molecular diagnoses using tissue obtained at earlier fetal ages. Until this is possible, fetal skin biopsy remains an important tool that can be used with reasonably high levels of safety and confidence.

Amniotic Fluid↗
PubMed1997

Direct cutaneous gene delivery in a human genetic skin disease.

The skin is an accessible somatic tissue for therapeutic gene transfer and, depending on therapeutic goals, a variety of cutaneous gene delivery approaches are currently available. Recent advances in direct injection of naked DNA into intact skin have shown promise and are less labor-intensive than approaches involving grafting of genetically modified cells. We have regenerated skin from transglutaminase 1 (TGase1)-deficient patients with the genetic skin disease lamellar ichthyosis (LI) on nude mice to examine the corrective impact of direct naked plasmid injection. Regenerated LI patient skin receiving repeated in vivo injections with a TGase1 expression plasmid displayed restoration of TGase1 expression in the correct tissue location in the suprabasal epidermis. Unlike LI skin regenerated from keratinocytes, first transduced in vitro with a retroviral expression vector for TGase1 prior to grafting, however, directly injected LI skin displayed a nonuniform TGase1 gene expression pattern. In further contrast, direct injection failed to correct the central histologic and functional abnormalities of the disease. These data demonstrate that partial restoration of gene expression can be achieved via direct injection of naked DNA in human genetic skin disease tissue but underscore the need for new advances to achieve efficient and sustained plasmid-based gene delivery to the skin.

Animals↗
PubMed1994

Genetic skin diseases.

Recent advances in molecular genetics have led to major breakthroughs in the understanding of two heterogeneous groups of inherited skin diseases, epidermolysis bullosa and the ichthyoses. Mutations in keratins K5 or K14 are found in epidermolysis bullosa simplex. The gravis (Herlitz) variety of junctional epidermolysis bullosa is characterized by defects in the anchoring filament protein kalinin. Both dominant and recessive forms of dystrophic epidermolysis bullosa appear to be due to mutations in the type VII collagen gene. Biochemical studies in patients with ichthyosis vulgaris reveal that the proteins profilaggrin and filaggrin are reduced or absent. Recessive X-linked ichthyosis is characterized by a deficiency of the enzyme steroid sulfatase. A type of lamellar ichthyosis may be explained on the basis of abnormal cornified cell envelope formation, and bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis) is caused by mutations in keratins K1 or K10.

Epidermolysis Bullosa↗
PubMed1991

Mutant keratin expression in transgenic mice causes marked abnormalities resembling a human genetic skin disease.

To explore the relationship between keratin gene mutations and genetic disease, we made transgenic mice expressing a mutant keratin in the basal layer of their stratified squamous epithelia. These mice exhibited abnormalities in epidermal architecture and often died prematurely. Blistering occurred easily, and basal cell cytolysis was evidence at the light and electron microscopy levels. Keratin filament formation was markedly altered, with keratin aggregates in basal cells. In contrast, terminally differentiating cells made keratin filaments and formed a stratum corneum. Recovery of outer layer cells was attributed to down-regulation of mutant keratin expression and concomitant induction of differentiation-specific keratins as cells terminally differentiate, and the fact that these cells arose from basal cells developing at a time when keratin expression was relatively low. Collectively, the pathobiology and biochemistry of the transgenic mice and their cultured keratinocytes bore a resemblance to a group of genetic disorders known as epidermolysis bullosa simplex.

Animals↗
PubMed1993

Genetic skin diseases caused by mutations in keratin intermediate filaments.

Keratin intermediate filaments are the major differentiation products of epithelial cells such as the epidermis. The filaments are highly dynamic entities involved in the maintenance of the structural integrity of both the individual cells and the entire tissue. Recent biochemical studies suggest that the keratin proteins overlap each other in several key locations when packed together in filaments. Interestingly, mutations that introduce inappropriate amino acid substitutions in at least some of these overlap regions cause defective keratin filaments that result in at least three classes of autosomal dominant skin disease.

Amino Acid Sequence↗
PubMed1999

Michel's medium: a potential alternative to cryoprotection for tissue transport in the investigation of genetic skin disease.

Michel's medium is now well established as a transport medium to maintain tissue-fixed immunoreactants prior to direct immunofluorescence and immunoelectron microscopy. This is a practical alternative to cryofixation prior to transportation when sending skin biopsies for the investigation of cutaneous immunobullous disease. In this study we have demonstrated preservation of the cutaneous basement membrane zone proteins in skin biopsies stored in Michel's medium for periods of up to 28 days - proving that Michel's medium can be used as a transport medium when sending skin biopsies for immunohistochemical studies to determine the structural and molecular deficiencies in genodermatoses such as inherited forms of epidermolysis bullosa.

Cryopreservation↗
PubMed1994

Genetic epidemiologic studies in the etiology of skin diseases.

Genetic epidemiologic studies have provided critical insights into the etiology of both rare and common skin diseases. Designs for these studies are distinct from those generally employed in epidemiologic studies. Here, we review the types of data collected for various genetic epidemiologic designs, inherent strengths and weaknesses, and their similarities to more classic epidemiologic methods. Examples from the study of skin diseases are provided to highlight the successful application of these methods.

Family Health↗
PubMed1996

The genetics of human skin diseases.

Molecular genetic analyses during the past half-decade have brought unexpected insights into the molecular defects underlying a wide variety of abnormal skin phenotypes. Highlights of the efforts in the past year include the identification of mutations in an epidermal transglutaminase gene in lamellar ichthyosis as well as mutations in an additional five keratin genes causing four different abnormal phenotypes, and mutations in beta 4 integrin and bullous pemphigoid antigen 2 genes in junctional epidermolysis bullosa and in the p16NK-4a gene in 50% of kindreds with familial melanoma.

Epidermolysis Bullosa, Junctional↗
PubMed1997

Sustainable cutaneous gene delivery.

Durable gene delivery to human skin is necessary for lasting correction of human genetic skin disease. Current cutaneous gene-delivery strategies, however, have achieved only transient gene expression, often only within a small percentage of tissue cells. The recent inability to sustain phenotypic correction of human genetic skin disease due to loss of therapeutic gene expression in regenerated epidermal tissue has highlighted this current limitation. In an effort to surmount this problem, we have generated gene delivery vectors that produce more durable gene delivery in human skin tissue in vivo.

Animals↗