Biomedical subjects

E H Epstein

Publications and source records attributed to E H Epstein.

At least 19 recordsLinked to original sources

PubMed1998

Activating Smoothened mutations in sporadic basal-cell carcinoma.

Basal-cell carcinomas (BCCs) are the commonest human cancer. Insight into their genesis came from identification of mutations in the PATCHED gene (PTCH) in patients with the basal-cell nevus syndrome, a hereditary disease characterized by multiple BCCs and by developmental abnormalities. The binding of Sonic hedgehog (SHH) to its receptor, PTCH, is thought to prevent normal inhibition by PTCH of Smoothened (SMO), a seven-span transmembrane protein. According to this model, the inhibition of SMO signalling is relieved following mutational inactivation of PTCH in basal-cell nevus syndrome. We report here the identification of activating somatic missense mutations in the SMO gene itself in sporadic BCCs from three patients. Mutant SMO, unlike wild type, can cooperate with adenovirus E1A to transform rat embryonic fibroblast cells in culture. Furthermore, skin abnormalities similar to BCCs developed in transgenic murine skin overexpressing mutant SMO. These findings support the role of SMO as a signalling component of the SHH-receptor complex and provide direct evidence that mutated SMO can function as an oncogene in BCCs.

Adenovirus E1A Proteins↗

PubMed1998

Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.

Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.

Amino Acid Sequence↗

PubMed1998

Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome.

Mutations in PATCHED (PTC), the human homolog of the Drosophila patched gene, have been identified in most exons of the gene in patients with the basal cell nevus syndrome and in sporadic basal cell carcinomas. We have screened the 23 PTC exons for mutations using single strand conformation polymorphism analysis of DNA from 86 basal cell nevus syndrome probands, 26 sporadic basal cell carcinomas, and seven basal cell nevus syndrome-associated basal cell carcinomas. This screen identified mutations located in eight exons in 13 of the basal cell nevus syndrome patients and in three of the tumors. The most common mutations were frameshifts resulting in premature chain termination. These results provide further evidence for the crucial role of PTC as a tumor suppressor in human keratinocytes.

Amino Acid Substitution↗

PubMed1997

Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors.

Patients with basal cell nevus syndrome have a high incidence of multiple basal cell carcinomas, medulloblastomas, and meningiomas. Because somatic PATCHED (PTCH) mutations have been found in sporadic basal cell carcinomas, we have screened for PTCH mutations in several types of sporadic extracutaneous tumors. We found that 2 of 14 sporadic medulloblastomas bear somatic nonsense mutations in one copy of the gene and also deletion of the other copy. In addition, we identified missense mutations in PTCH in two of seven breast carcinomas, one of nine meningiomas, and one colon cancer cell line. No PTCH gene mutations were detected in 10 primary colon carcinomas and eighteen bladder carcinomas.

Amino Acid Sequence↗

PubMed1997

Basal cell carcinomas in mice overexpressing sonic hedgehog.

Mutations in the tumor suppressor gene PATCHED (PTC) are found in human patients with the basal cell nevus syndrome, a disease causing developmental defects and tumors, including basal cell carcinomas. Gene regulatory relationships defined in the fruit fly Drosophila suggest that overproduction of Sonic hedgehog (SHH), the ligand for PTC, will mimic loss of ptc function. It is shown here that transgenic mice overexpressing SHH in the skin develop many features of basal cell nevus syndrome, demonstrating that SHH is sufficient to induce basal cell carcinomas in mice. These data suggest that SHH may have a role in human tumorigenesis.

Animals↗

PubMed1997

Partial dominance of a keratin 14 mutation in epidermolysis bullosa simplex--increased severity of disease in a homozygote.

Epidermolysis bullosa simplex is a disease in which keratin gene mutations cause the production of defective intermediate filaments, which leads in turn to epidermal basal cell fragility and blistering. The inheritance in nearly all kindreds is autosomal dominant, most kindreds have missense mutations, and the encoded proteins appear to exert a dominant negative function. One previously reported patient with generalized blistering had a fully dominant mutation of keratin 5; in that kindred a homozygote was affected no more severely than the heterozygotes. By contrast we report here a keratin 14 mutation that causes blistering limited to the hands and feet in heterozygotes, but homozygotes have more severe, widespread blistering of the skin and mucous membranes. Thus keratin gene mutations may be not only fully recessive or fully dominant but also partially dominant as well.

Adolescent↗

PubMed1996

Human homolog of patched, a candidate gene for the basal cell nevus syndrome.

The basal cell nevus syndrome (BCNS) is characterized by developmental abnormalities and by the postnatal occurrence of cancers, especially basal cell carcinomas (BCCs), the most common human cancer. Heritable mutations in BCNS patients and a somatic mutation in a sporadic BCC were identified in a human homolog of the Drosophila patched (ptc) gene. The ptc gene encodes a transmembrane protein that in Drosophila acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues. The human PTC gene appears to be crucial for proper embryonic development and for tumor suppression.

Adult↗

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↗

PubMed1996

Localization of the Darier disease gene to a 2-cM portion of 12q23-24.1.

Positional cloning with microsatellite markers allowed further localization of the Darier disease gene to a 2-cM interval of chromosome 12, 12q23-24.1, between the polymorphic loci D12S234 and D12S129. A region this size is suitable for construction of a contig to identify the Darier disease gene. Use of a polymorphic intronic marker for nitric oxide synthetase 1 gene, which maps to the same chromosomal area as the Darier gene, allowed exclusion of that gene as the Darier disease gene.

Chromosome Mapping↗

PubMed1996

Genetic basis of Bart's syndrome: a glycine substitution mutation in type VII collagen gene.

Bart's syndrome was initially described as a genodermatosis characterized by congenital localized absence of the skin, together with blistering and nail abnormalities. Recent analysis of Bart's original kindred demonstrated ultrastructural abnormalities in the anchoring fibrils and linkage of the inheritance of the disease to the region of chromosome 3 near the type VII collagen gene (COL7A1). We have performed mutation analysis in this family by using electrophoretic heteroduplex analysis followed by direct nucleotide sequencing of DNA. These results disclosed a G-to-A transition within exon 73 of COL7A1, which results in a glycine-to-arginine substitution within the triple-helical domain of type VII collagen in affected individuals. In this family, these findings demonstrate that Bart's syndrome is a clinical variant of dominant dystrophic epidermolysis bullosa.

Amino Acid Sequence↗

PubMed1996

Genetic basis of Bart's syndrome: a glycine substitution mutation in the type VII collagen gene.

Amino Acid Sequence↗

PubMed1995

Bart's syndrome. Ultrastructure and genetic linkage.

BACKGROUND AND DESIGN: Bart's syndrome, originally described in a large family in 1966, consists of congenital localized absence of skin, blistering, and associated nail abnormalities. Since then, several descriptions of patients with similar clinical findings have suggested that this syndrome may represent any of the three subtypes of epidermolysis bullosa: epidermal, junctional, or dermal. Because no histologic or ultrastructural studies were done in Bart's kindred, and neither immunohistologic nor genetic linkage technology was available at that time, classification of the syndrome has been unclear. We report the findings of clinical, ultrastructural, immunohistologic, and genetic linkage studies of the original kindred and their descendants. We contacted original family members and their descendants by telephone and questionnaire. Skin biopsy specimens adjacent to blisters were obtained for ultrastructural and immunochemical analysis. Blood samples were drawn from affected members and their spouses and children for genetic linkage studies. RESULTS: The clinical findings seen in the descendants of the original family with Bart's syndrome were similar to those described in 1966. We did, however, detect persistence of blistering into adult life and mild atrophic scarring and milia formation at sites of blistering in some family members, a finding not noted in the original study. Hypertrophic scarring and albopapuloid lesions were not detected. Ultrastructural analysis of skin from affected family members showed poorly formed anchoring fibrils and cleavage below the lamina densa. Immunohistochemical staining localized type IV collagen at the roof of blistered skin. Staining for type VII collagen was found to have a normal distribution in nonblistered skin. Genetic linkage studies mapped the gene for the disease in this family to chromosome 3p at or near the site of the gene encoding type VII collagen. CONCLUSION: Bart's syndrome is a subtype of dominantly inherited dystrophic epidermolysis bullosa.

Adult↗

PubMed1995

Keratin 14 gene mutations in patients with epidermolysis bullosa simplex.

Mutations in genes encoding the keratin intermediate filaments expressed in basal cells have been identified in some families with epidermolysis bullosa simplex as the proximate cause of the fragility. We have systematically scanned genomic sequences of one of these keratins, keratin 14, for mutations in patients from 49 apparently independent kindreds using single-strand conformation polymorphism analysis. The ten mutations identified are clustered at three sites--the ends of the helices and the L12 linker region, mutation sites that have been identified in past, more limited studies. Early onset of blistering in these ten families is correlated with more widespread distribution of lesions.

Age of Onset↗

PubMed1994

Herlitz's junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the gamma 2 subunit of nicein/kalinin (LAMININ-5).

We have linked Herlitz's junctional epidermolysis bullosa (H-JEB) to the gene (LAMC2) encoding the gamma 2 subunit of nicein/kalinin, an isolaminin (laminin-5) expressed by basal keratinocytes. In four H-JEB kindreds, a maximum two-point lod score of 5.33 at theta = 0 was observed between a microsatellite near LAMC2 at 1q25-31 and the disease. In one family, a homozygous point mutation leading to a premature stop codon (CGA to TGA) was identified in exon 3 of the gene. The segregation of the mutated allele implicates the mutation in the pathology of the disorder and corroborates the linkage results.

Base Sequence↗

PubMed1994

Parental origin of chromosome 9q22.3-q31 lost in basal cell carcinomas from basal cell nevus syndrome patients.

The basal cell nevus syndrome is an autosomal dominant disease, one of the most prominent phenotypic features of which is a large number of cutaneous basal cell carcinomas. The gene whose mutation underlies this disease has been mapped to chromosome 9q22.3-q31, and basal cell carcinomas frequently have allelic losses including this site. We report here that the chromosome 9q22.3-q31 lost in 24 basal cell carcinomas from basal cell nevus syndrome patients was the one predicted by linkage to contain the wild-type gene. Hence these data are compatible with the exception that the product of the basal cell nevus syndrome gene acts as a tumor suppressor.

Alleles↗

PubMed1994

Localization of the gene whose mutations underlie Hailey-Hailey disease to chromosome 3q.

Hailey-Hailey disease (familial benign chronic pemphigus) is an autosomal dominant skin disease characterized by impaired keratinocyte cohesion and consequent blister formation. In the present study we have used linkage analysis to map the gene for this disease to a region of chromosome 3q between D3S1589 and D3S1316. The maximum combined two point lod score in four families studied was 14.60 at theta = 0 at the D3S1290 microsatellite repeat. These findings suggest the presence of a gene not previously known to be involved in keratinocyte cohesion at this site.

Chromosome Mapping↗

PubMed1994

Hailey-Hailey disease is not allelic to Darier's disease.

Hailey-Hailey (Familial Benign Chronic Pemphigus) Disease is a rare autosomal dominant disorder characterized by blisters caused by suprabasal epidermal acantholysis. Another autosomal dominant skin disease, Darier's disease, has clinical and histologic features which overlap those of Hailey-Hailey disease and recently has been mapped to chromosome 12q23-q24.1. We have used linkage analysis to test whether or not a mutation in this region might also underlie Hailey-Hailey disease. This analysis, using polymorphic loci tightly linked to Darier's disease, excluded this region as the site for the disease-causing mutation in two kindreds affected with Hailey-Hailey disease.

Adolescent↗

PubMed1994

Mutations of keratin 9 in two families with palmoplantar epidermolytic hyperkeratosis.

The hereditary palmoplantar keratodermas are a heterogeneous group of diseases unified by thickening of the stratum corneum of the palms and soles with consequent painful fissuring, discomfort on pressure, and resultant disability. One of the histologic patterns underlying palmoplantar hyperkeratosis is that of epidermolytic hyperkeratosis. Because that histologic pattern has been found in its generalized form to be due to keratin gene mutations, we assessed the inheritance of the form localized to the palms and soles. In each of two families studied, the mutant gene causing the disease is linked strongly to the chromosome 17 cluster of genes encoding type I keratins, and mutations are present in the conserved helix initiation region of keratin 9 in affected members of both kindreds. These data, as well as those generated recently by others, indicate that keratin gene mutations may underlie not only the generalized phenotype but also this more localized phenotype of epidermolytic hyperkeratosis and suggest one mechanism by which skin diseases can achieve their characteristic localization.

Base Sequence↗