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1.
Mech Dev ; 79(1-2): 57-72, 1998 Dec.
Article in English | MEDLINE | ID: mdl-10349621

ABSTRACT

The Drosophila slit gene (sli) encodes a secreted leucine-rich repeat-containing protein (slit) expressed by the midline glial cells and required for normal neural development. A putative human sli homolog, SLIT1, has previously been identified by EST database scanning. We have isolated a second human sli homolog, SLIT2, and its murine homolog Slit2. Both SLIT1 and SLIT2 proteins show approximately 40% amino acid identity to slit and 60% identity to each other. In mice, both genes are expressed during CNS development in the floor plate, roof plate and developing motor neurons. As floor plate represents the vertebrate equivalent to the midline glial cells, we predict a conservation of function for these vertebrate homologs. Each gene shows additional but distinct sites of expression outside the CNS suggesting a variety of functions for these proteins.


Subject(s)
Central Nervous System/embryology , Drosophila Proteins , Gene Expression Regulation, Developmental , Nerve Tissue Proteins/genetics , Amino Acid Sequence , Animals , Brain/embryology , Cell Line , Cloning, Molecular , Embryo, Mammalian/metabolism , Embryo, Nonmammalian , Expressed Sequence Tags , Extremities/embryology , Female , Humans , In Situ Hybridization , Infant, Newborn , Intercellular Signaling Peptides and Proteins , Male , Mice , Molecular Sequence Data , Nerve Tissue Proteins/metabolism , Sequence Analysis , Sequence Homology, Amino Acid , Spinal Cord/embryology , Spinal Cord/growth & development , Urogenital System/growth & development , Vertebrates
2.
Am J Hum Genet ; 60(1): 21-6, 1997 Jan.
Article in English | MEDLINE | ID: mdl-8981943

ABSTRACT

The human homologue of the Drosophila segment polarity gene patched is implicated in the development of nevoid basal cell carcinoma syndrome (NBCCS) and in the genesis of sporadic basal cell carcinomas. In order to examine the phenotypic variability in NBCCS and to highlight functionally important domains of the PTCH protein, we have now screened 71 unrelated NBCCS individuals for mutations in the PTCH exons. We identified 28 mutations that are distributed throughout the entire gene, and most (86%) cause protein truncation. As part of this analysis, we demonstrate that failure of one NBCCS family to show clear linkage to chromosome 9q22.3-31 is most likely due to germinal mosaicism. We have identified three families bearing identical mutations with variable phenotypes, suggesting phenotypic variability in NBCCS is a complex genetic event. No phenotype genotype correlation between the position of truncation mutations and major clinical features was evident. Two missense mutations have been identified, and their location within transmembrane domains supports the notion that PTCH may have a transport function. The preponderance of truncation mutants in the germ line of NBCCS patients suggests that the developmental defects associated with the disorder are most likely due to haploinsufficiency.


Subject(s)
Basal Cell Nevus Syndrome/genetics , Germ-Line Mutation , Membrane Proteins/genetics , Exons , Female , Genotype , Humans , Male , Molecular Sequence Data , Mosaicism , Patched Receptors , Patched-1 Receptor , Pedigree , Phenotype , Polymorphism, Single-Stranded Conformational , Receptors, Cell Surface , Transcription, Genetic
3.
Cell ; 85(6): 841-51, 1996 Jun 14.
Article in English | MEDLINE | ID: mdl-8681379

ABSTRACT

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.


Subject(s)
Basal Cell Nevus Syndrome/genetics , Drosophila Proteins , Genes, Tumor Suppressor/genetics , Insect Hormones/genetics , Membrane Proteins/genetics , Sequence Homology, Nucleic Acid , Alleles , Animals , Base Sequence , Chromosome Mapping , Chromosomes, Human, Pair 9 , Cloning, Molecular , DNA, Complementary/genetics , Drosophila/genetics , Exons/genetics , Female , Gene Deletion , Gene Expression , Humans , In Vitro Techniques , Introns/genetics , Molecular Sequence Data , Mutation/genetics , Pedigree , Receptors, Cell Surface
4.
Cytogenet Cell Genet ; 72(4): 306-9, 1996.
Article in English | MEDLINE | ID: mdl-8641136

ABSTRACT

The Wilms' tumor suppressor 1 gene (WT1) encodes a zinc finger transcription factor critical for normal urogenital development. We have previously isolated a DNA fragment, +P5 (D1S3309E), to which all WT1 protein isoforms bind. Using PCR of a human x rodent somatic cell hybrid mapping panel, together with two-color fluorescence in situ hybridisation of +P5-containing cosmids and previously localised human chromosome 1q cosmids, we have mapped the +P5 fragment to chromosome 1q21-->q22.


Subject(s)
Chromosomes, Human, Pair 1/genetics , DNA-Binding Proteins/genetics , DNA/genetics , DNA/metabolism , Genes, Wilms Tumor , Transcription Factors/genetics , Zinc Fingers/genetics , Animals , Base Sequence , Binding Sites/genetics , Chromosome Mapping , Chromosomes, Human, Pair 1/ultrastructure , Cosmids , DNA Primers/genetics , Humans , Hybrid Cells , In Situ Hybridization, Fluorescence , Molecular Sequence Data , Polymerase Chain Reaction , WT1 Proteins
5.
Cytogenet Cell Genet ; 68(1-2): 119-21, 1995.
Article in English | MEDLINE | ID: mdl-7956349

ABSTRACT

The human growth-arrest specific gene GAS1 maps to chromosome bands 9q21.3-->q22, the region known to contain the tumour suppressor gene responsible for nevoid basal cell carcinoma syndrome (NBCCS). Because of its putative action as a tumour suppressor gene, the GAS1 gene was analysed as a candidate for the NBCCS gene. Using two-colour fluorescence in situ hybridization, the GAS1 gene maps outside the interval which, by genetic analysis, has been shown to contain the NBCCS gene.


Subject(s)
Basal Cell Nevus Syndrome/genetics , Chromosomes, Human, Pair 9 , Hominidae/genetics , Repressor Proteins/genetics , Animals , Cells, Cultured , Chromosome Mapping , Cosmids , Humans , In Situ Hybridization/methods , In Situ Hybridization, Fluorescence , Lymphocytes/cytology , Multigene Family
6.
Pediatrics ; 68(4): 579-82, 1981 Oct.
Article in English | MEDLINE | ID: mdl-7322691

ABSTRACT

Children have died from heat stress because they have been left in closed automobiles. Changes in the internal temperature of various sized automobiles left in the Brisbane summer sun were examined. With all windows and doors closed, this temperature rose from an ambient level of 36 C to a maximum of 67 C within 15 minutes and remained there until the doors were opened. Slightly lower temperatures were found for light colored sedans and station wagons. However, all readings were significantly above ambient and all produced an environment unacceptable for a child. Temperatures approaching ambient were only achieved with ventilation provided by windows at least 200 mm (half) open. A lesser gap (50 mm) resulted in interior temperatures exceeding 50 C, which is still too hot for children. Infants left in such an environment will lose fluid quickly from sweat and could become as much as 8% dehydrated in four hours. Subsequently the cerebral manifestations of heat stroke would ensue. Parents and pediatricians should be warned of the danger of heat stress if children are left in a closed automobile.


Subject(s)
Automobiles , Heat Exhaustion/etiology , Australia , Dehydration/etiology , Heat Exhaustion/physiopathology , Humans , Humidity , Infant , Seasons , Temperature , Ventilation , Water Loss, Insensible , Weather
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