Biomedical subjects
K B Avraham
Publications and source records attributed to K B Avraham.
Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans.
The molecular basis for autosomal dominant progressive nonsyndromic hearing loss in an Israeli Jewish family, Family H, has been determined. Linkage analysis placed this deafness locus, DFNA15, on chromosome 5q31. The human homolog of mouse Pou4f3, a member of the POU-domain family of transcription factors whose targeted inactivation causes profound deafness in mice, was physically mapped to the 25-centimorgan DFNA15-linked region. An 8-base pair deletion in the POU homeodomain of human POU4F3 was identified in Family H. A truncated protein presumably impairs high-affinity binding of this transcription factor in a dominant negative fashion, leading to progressive hearing loss.
Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally.
Homozygous targeted disruption of the mouse Caspase 8 (Casp8) gene was found to be lethal in utero. The Caspase 8 null embryos exhibited impaired heart muscle development and congested accumulation of erythrocytes. Recovery of hematopoietic colony-forming cells from the embryos was very low. In fibroblast strains derived from these embryos, the TNF receptors, Fas/Apo1, and DR3 were able to activate the Jun N-terminal kinase and to trigger IkappaB alpha phosphorylation and degradation. They failed, however, to induce cell death, while doing so effectively in wild-type fibroblasts. These findings indicate that Caspase 8 plays a necessary and nonredundant role in death induction by several receptors of the TNF/NGF family and serves a vital role in embryonal development.
Hear come more genes!
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Deafness. Sounds from the cochlea.
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Motors, channels and the sounds of silence.
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Characterization of unconventional MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice.
Deafness is the most common form of sensory impairment in humans. Mutations in unconventional myosins have been found to cause deafness in humans and mice. The mouse recessive deafness mutation, Snell's waltzer, contains an intragenic deletion in an unconventional myosin, myosin VI (locus designation, Myo6). The requirement for Myo6 for proper hearing in mice makes this gene an excellent candidate for a human deafness disorder. Here we report the cloning and characterization of the human unconventional myosin VI (locus designation, MYO6) cDNA. The MYO6 gene maps to human chromosome 6q13. The isolation of the human gene makes it now possible to determine if mutations in MYO6 contribute to the pathogenesis of deafness in the human population.
Mapping of unconventional myosins in mouse and human.
Myosins are molecular motors that move along filamentous actin. Seven classes of myosin are expressed in vertebrates: conventional myosin, or myosin-II, as well as the 6 unconventional myosin classes-I, -V, -VI, -VII, -IX, and -X. We have mapped in mouse 22 probes encompassing all known unconventional myosins and, as a result, have identified 16 potential unconventional myosin genes. These genes include 7 myosins-I, 2 myosins-V, 1 myosin-VI, 3 myosins-VII, 2 myosins-IX, and 1 myosin-X. The map location of 5 of these genes was identified in human chromosomes by fluorescence in situ hybridization.
Identification and chromosomal localization of Atm, the mouse homolog of the ataxia-telangiectasia gene.
Atm, the mouse homolog of the human ATM gene defective in ataxia-telangiectasia (A-T), has been identified. The entire coding sequence of the Atm transcript was cloned and found to contain an open reading frame encoding a protein of 3066 amino acids with 84% overall identity and 91% similarity to the human ATM protein. Variable levels of expression of Atm were observed in different tissues. Fluorescence in situ hybridization and linkage analysis located the Atm gene on mouse chromosome 9, band 9C, in a region homologous to the ATM region on human chromosome 11q22-q23.
The characterization and localization of the mouse thymopoietin/lamina-associated polypeptide 2 gene and its alternatively spliced products.
Thymopoietins (Tmpos) are a group of ubiquitously expressed nuclear proteins, with sequence homology to lamina-associated polypeptide 2 (LAP2). Here we report the isolation and characterization of seven mouse Tmpo mRNA transcripts named Tmpo alpha, beta, beta', gamma, epsilon, delta, and zeta. The alpha, beta, and gamma Tmpo cDNA clones are the mouse homologs of the previously characterized human alpha, beta, and gamma TMPOs, respectively, whereas Tmpo epsilon, delta, and zeta are novel cDNAs. Additionally, the mouse Tmpo gene was cloned and characterized. It is a single-copy gene organized in 10 exons spanning approximately 22 kb, which encodes all of the described Tmpo cDNA sequences, located in the central region of mouse chromosome 10. The almost identical genomic organization between the human and mouse genes, and the novel alternatively spliced mouse transcripts, led us to reanalyze the human TMPO gene. The human beta-specific domain was found to be encoded by 3 exons designated 6a, 6b, and 6c and not by a single exon as described previously. These findings suggest that there may be more human transcripts than currently recognized. The possible involvement of the new growing family of Tmpo proteins in nuclear architecture and cell cycle control is discussed.
Chromosomal organization and transcriptional regulation of human GEM and localization of the human and mouse GEM loci encoding an inducible Ras-like protein.
The mitogen-induced gene, GEM, encodes a GTP-binding protein that belongs to a new family within the Ras superfamily. The regulated expression pattern of Gem suggests a role for this protein in cellular responses to growth stimulation. To facilitate the assessment of the possible role of GEM in heritable and spontaneous disease processes, the genomic organization of human GEM and the chromosomal localization of human and murine GEM have been determined. GEM has been localized to the long arm of human chromosome 8 (8q13-q21) between the D8S85 and CA2 loci by genetic linkage analysis using an MspI restriction fragment length polymorphism within GEM. No consistent somatic chromosomal alterations or heritable diseases are associated with this region. Mouse Gem maps to the proximal region of chromosome 4 between Mos and Cga. To gain insight into the transcriptional regulation of GEM, we have established the transcriptional initiation site of GEM in human T cells and defined a 5' upstream region sufficient for mitogen-responsive, inducible transcription.
cDNA cloning, tissue distribution, and chromosomal localization of Ocp2, a gene encoding a putative transcription-associated factor predominantly expressed in the auditory organs.
We report the cloning of the Ocp2 gene encoding OCP-II from a guinea pig organ-of-Corti cDNA library. The predicted open reading frame encodes a protein of 163 amino acids with an estimated molecular mass of 18.6 kDa. A homology search revealed that Ocp2 shares significant sequence similarity with p15, a subunit of transcription factor SIII that regulates the activity of the RNA polymerase II elongation complex. The Ocp2 messenger RNA is expressed abundantly in the cochlea while not significantly in any other tissues examined, including brain, eye, heart, intestine, kidney, liver, lung, thigh muscle, and testis, demonstrating that the expression of this gene may be restricted to auditory organs. A polyclonal antiserum was raised against the N-terminal region of OCP-II. Immunohistochemical staining of paraffin-embedded sections of the cochlea showed that OCP-II is localized abundantly in nonsensory cells in the organ of Corti; in addition, it was also detected, at a lower concentration, in vestibular sensory organs, as well as auditory and vestibular brain stem nuclei. The Ocp2 gene was mapped to mouse chromosome 4 as well as 11. Our results suggest that OCP-II may be involved in transcription regulation for the development or maintenance of specialized functions of the inner ear.
Murine chromosomal location of eight members of the hepatocyte nuclear factor 3/fork head winged helix family of transcription factors.
A 100-amino-acid DNA-binding motif, known as the winged helix, was first identified in the mammalian hepatocyte nuclear factor-3 (HNF-3) and Drosophila fork head family of transcription factors. Subsequently, more than 40 different genes that contain the winged helix motif have been identified. In the studies described here, we have determined the murine chromosomal location of eight members of this gene family, HFH-1, HFH-3, HFH-4, HFH-5, HFH-6, HFH-8, BF-1, and BF-2, by interspecific backcross analysis. These genes, designated HNF-3 fork head homolog 1 (Hfh1), Hfh3, Hfh4, Hfh5, Hfh6, Hfh8, Hfh9, and Hfh10, respectively, mapped to 6 different mouse autosomes and are thus well dispersed throughout the mouse genome. Based on this mapping information, we predict the chromosomal location of these genes in humans and discuss the potential of these genes as candidates for uncloned mouse mutations.
Mapping of the mouse homolog of the human runt domain gene, AML2, to the distal region of mouse chromosome 4.
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The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells.
The mouse represents an excellent model system for the study of genetic deafness in humans. Many mouse deafness mutants have been identified and the anatomy of the mouse and human ear is similar. Here we report the use of a positional cloning approach to identify the gene encoded by the mouse recessive deafness mutation, Snell's waltzer (sv). We show that sv encodes an unconventional myosin heavy chain, myosin VI, which is expressed within the sensory hair cells of the inner ear, and appears to be required for maintaining their structural integrity. The requirement for myosin VI in hearing makes this gene an excellent candidate for a human deafness disorder.
Mapping of murine fibroblast growth factor receptors refines regions of homology between mouse and human chromosomes.
The genes for the fibroblast growth factor receptors Fgfr2, Fgfr3, and Fgfr4 have been mapped in the mouse using an interspecific backcross mapping panel. The Fgfr loci map to previously defined regions of homology between human and mouse chromosomes and provide additional information regarding human/mouse comparative mapping.
Cell damage by excess CuZnSOD and Down's syndrome.
Down's Syndrome (DS), the phenotypic expression of human trisomy 21, is presumed to result from overexpression of certain genes residing on chromosome 21 at the segment 21q22-the Down locus. The "housekeeping" enzyme CuZn-superoxide dismutase (CuZnSOD) is encoded by a gene from that region and its activity is elevated in DS patients. Moreover, the recent discovery that familial ALS is associated with mutations in the gene encoding CuZnSOD, focused attention on the entanglement of oxygen-free radicals in cell death and neuronal disorders. To investigate the involvement of CuZnSOD gene dosage in the etiology of the syndrome we have developed both cellular and animal models which enabled us to investigate the physiological consequences resulting from overexpression of the CuZnSOD gene. Rat PC12 cells expressing elevated levels of transfected human CuZnSOD gene were generated. These transformants (designated PC12-hSOD) closely resembled the parental cells in their morphology, growth rate, and response to nerve growth factor, but showed impaired neurotransmitter uptake. The lesion was localized to the chromaffin granule transport mechanism. These results show that elevation of CuZnSOD activity interferes with the transport of biogenic amines into chromaffin granules. Since neurotransmitter uptake plays an important role in many processes of the central nervous system, CuZnSOD gene-dosage may contribute to the neurobiological abnormalities of Down's Syndrome. As an approach to the development of an animal model for Down's Syndrome, several strains of transgenic mice which carry the human CuZnSOD gene have been prepared. These animals express the transgene as an active enzyme with increased activity from 1.6 to 6.0-fold in the brains of four transgenic strains and to an equal or lesser extent in several other tissues. To investigate the contribution of CuZnSOD gene dosage in the neuropathological symptoms of Down's Syndrome, we analyzed the tongue muscle of the transgenic-CuZnSOD mice. The tongue neuromuscular junctions (NMJ) in the transgenic animals exhibited significant pathological changes; withdrawal and destruction of some terminal axons and the development of multiple small terminals. The ratio of terminal axon area to postsynaptic membranes decreased, and secondary folds were often complex and hyperplastic. The morphological changes in the transgenic NMJ were similar to those previously seen in the transgenic NMJ and were similar to those previously seen in muscles of aging mice and rats as well as in tongue muscles of patients with Down's Syndrome. The findings suggest that CuZnSOD gene dosage is involved in the pathological abnormalities of tongue NMJ observed in Down's Syndrome patients.(ABSTRACT TRUNCATED AT 400 WORDS)
Murine chromosomal location of four class III POU transcription factors.
A family of mouse genes encoding class III POU transcription factors consists of four members: Oct-6, Brn-2, Brn-1, and Brn-4. In accordance with mouse nomenclature, these loci have been designated Otf-6, Otf-7, Otf-8, and Otf-9, respectively. While the four genes share a highly conserved class III POU domain, the remaining regions are considerably diverged from each other. The POU domains of these transcription factors recognize the octamer-motif sequence and possess a similar DNA-binding specificity. Chromosomal mapping has demonstrated that the four genes are unlinked: Otf-6 is located on the distal region of chromosome 4, Otf-7 on the proximal region of chromosome 4, Otf-8 on chromosome 1, and Otf-9 on the X chromosome.