ABSTRACT
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.
Subject(s)
Basal Cell Nevus Syndrome/genetics , Drosophila Proteins , Insect Proteins/genetics , Membrane Proteins/genetics , Mutation , Amino Acid Sequence , Base Sequence , Breast Neoplasms/genetics , Chromosome Deletion , Chromosomes, Human, Pair 9/genetics , Colonic Neoplasms/genetics , Female , Heterozygote , Humans , Medulloblastoma/genetics , Meningioma/genetics , Receptors, Cell Surface , Tumor Cells, Cultured , Urinary Bladder Neoplasms/geneticsABSTRACT
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.
Subject(s)
Basal Cell Nevus Syndrome/genetics , Drosophila Proteins , Genes, Tumor Suppressor , Membrane Proteins/genetics , Adult , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , DNA, Neoplasm , Drosophila , Female , Frameshift Mutation , Humans , Insect Hormones/genetics , Male , Middle Aged , Molecular Sequence Data , Patched Receptors , Patched-1 Receptor , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Protein Conformation , Receptors, Cell SurfaceABSTRACT
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.
Subject(s)
Alleles , Darier Disease/genetics , Pemphigus, Benign Familial/genetics , Adolescent , Adult , Carrier Proteins/genetics , Chromosome Mapping , Chromosomes, Human, Pair 12 , Cytoskeletal Proteins/genetics , Desmoplakins , Family Health , Female , Genetic Linkage , Genotype , Humans , Hyaluronan Receptors , Keratins/genetics , Male , Membrane Proteins/genetics , Middle Aged , Mutation , Pedigree , Receptors, Cell Surface/genetics , Receptors, Lymphocyte Homing/geneticsABSTRACT
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.
Subject(s)
Basal Cell Nevus Syndrome/genetics , Chromosome Deletion , Chromosomes, Human, Pair 9 , Alleles , Genes, Tumor Suppressor , HumansABSTRACT
Ichthyosis hystrix Curth-Macklin is a rare autosomal dominant disease characterized clinically by hyperkeratosis and ultrastructurally by disruption of the keratin intermediate filament network of suprabasal keratinocytes. We have used linkage analysis to test whether a keratin gene mutation might underlie this disease. This analysis excluded the keratin gene loci as the sites for the disease-causing mutation in one affected kindred.
Subject(s)
Ichthyosis/genetics , Keratins/genetics , Mutation , Chromosomes, Human, Pair 12 , Family Health , Female , Humans , Male , PedigreeABSTRACT
Bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis) is a severe, generalized, lifelong disease of the skin. As in epidermolysis bullosa simplex, intraepidermal blisters and clumping of keratin intermediate filaments are characteristic. We report here linkage of the inheritance of this disease to the region of chromosome 12q containing the genes encoding type II keratins. This suggests that keratin gene mutations may underlie this complex hyperproliferative and hyperkeratotic phenotype.
Subject(s)
Chromosomes, Human, Pair 12 , Hyperkeratosis, Epidermolytic/genetics , Keratins/genetics , Chromosome Mapping , Epidermolysis Bullosa Simplex/genetics , Female , Genetic Linkage , Humans , Male , Pedigree , PhenotypeABSTRACT
Keratin 5 is the major type II keratin of the basal cells of epidermis and of other stratified epithelia. With its type I partner, keratin 14, it constitutes a major fraction of the cytoskeleton of the basal cells. Because the inheritance of epidermolysis bullosa simplex, a disease of epidermal basal cell fragility, was mapped in one family to chromosome 12q close to D12S14, we undertook to localize the gene for keratin 5. Polymerase chain reaction analysis of somatic cell hybrids mapped the keratin 5 gene to chromosome 12, and multicolor fluorescence in situ hybridization localized it to 12q very near D12S14. This sublocalization exemplifies the utility of in situ physical localization in assessing the candidacy of genes thought to underlie inherited disorders.
Subject(s)
Chromosomes, Human, Pair 12 , Epidermolysis Bullosa Simplex/genetics , Keratins/genetics , Nucleic Acid Hybridization , Polymerase Chain Reaction , Animals , Base Sequence , Cricetinae , Fluorescent Dyes , Genetic Markers , Humans , Hybrid Cells , Lod Score , Molecular Sequence DataABSTRACT
Basal cell carcinomas, the most common human tumors, generally appear sporadically and in small numbers. Rarely, they may appear in great numbers and at an earlier age as a manifestation of the basal cell nevus syndrome, an autosomal dominant inherited disorder. Drawing on the retinoblastoma paradigm, we have begun a search for tumor suppressor genes important in the development of basal cell carcinomas by comparing DNA of tumors and normal cells. Loss of heterozygosity, a frequent marker of the site of tumor suppressor genes, was found at chromosome 1q in one-third of the tumors studied. However, comparison of the inheritance of DNA markers versus the inheritance of the basal cell nevus syndrome is one large kindred excluded this area of chromosome 1q as the site of the gene whose abnormality causes this hereditary disease. These data suggest that large deletions may accompany the development of cutaneous, low grade tumors just as they accompany the development of visceral, high grade cancers.
Subject(s)
Basal Cell Nevus Syndrome/genetics , Carcinoma, Basal Cell/genetics , Chromosomes, Human, Pair 1 , Genes, Suppressor , Heterozygote , Adult , Aged , Aged, 80 and over , Chromosome Mapping , Genetic Linkage , Humans , Middle Aged , PedigreeABSTRACT
A cDNA clone encoding a portion of Drosophila nuclear lamins Dm1 and Dm2 has been identified by screening a lambda-gt11 cDNA expression library using Drosophila lamin-specific monoclonal antibodies. Two different developmentally regulated mRNA species were identified by Northern blot analysis using the initial cDNA as a probe, and full-length cDNA clones, apparently corresponding to each message, have been isolated. In vitro transcription of both full-length cDNA clones in a pT7 transcription vector followed by in vitro translation in wheat germ lysate suggests that both clones encode lamin Dm0, the polypeptide precursor of lamins Dm1 and Dm2. Nucleotide sequence analyses confirm the impression that both cDNA clones code for the identical polypeptide, which is highly homologous with human lamins A and C as well as with mammalian intermediate filament proteins. The two clones differ in their 3'-untranslated regions. In situ hybridization of lamin cDNA clones to Drosophila polytene chromosomes shows only a single locus of hybridization at or near position 25F on the left arm of chromosome 2. Southern blot analyses of genomic DNA are consistent with the notion that a single or only a few highly similar genes encoding Drosophila nuclear lamin Dm0 exist in the genome.