References of "Fuchs, H"
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See detailThe Notch ligand Jagged1 is required for inner ear sensory development.
Kiernan, A. E.; Ahituv, N.; Fuchs, H. et al

in Proceedings of the National Academy of Sciences of the United States of America (2001), 98(7), 3873-8

Within the mammalian inner ear there are six separate sensory regions that subserve the functions of hearing and balance, although how these sensory regions become specified remains unknown. Each sensory ... [more ▼]

Within the mammalian inner ear there are six separate sensory regions that subserve the functions of hearing and balance, although how these sensory regions become specified remains unknown. Each sensory region is populated by two cell types, the mechanosensory hair cell and the supporting cell, which are arranged in a mosaic in which each hair cell is surrounded by supporting cells. The proposed mechanism for creating the sensory mosaic is lateral inhibition mediated by the Notch signaling pathway. However, one of the Notch ligands, Jagged1 (Jag1), does not show an expression pattern wholly consistent with a role in lateral inhibition, as it marks the sensory patches from very early in their development--presumably long before cells make their final fate decisions. It has been proposed that Jag1 has a role in specifying sensory versus nonsensory epithelium within the ear [Adam, J., Myat, A., Roux, I. L., Eddison, M., Henrique, D., Ish-Horowicz, D. & Lewis, J. (1998) Development (Cambridge, U.K.) 125, 4645--4654]. Here we provide experimental evidence that Notch signaling may be involved in specifying sensory regions by showing that a dominant mouse mutant headturner (Htu) contains a missense mutation in the Jag1 gene and displays missing posterior and sometimes anterior ampullae, structures that house the sensory cristae. Htu/+ mutants also demonstrate a significant reduction in the numbers of outer hair cells in the organ of Corti. Because lateral inhibition mediated by Notch predicts that disruptions in this pathway would lead to an increase in hair cells, we believe these data indicate an earlier role for Notch within the inner ear. [less ▲]

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See detailAey2, a new mutation in the betaB2-crystallin-encoding gene of the mouse.
Graw, J.; Loster, J.; Soewarto, D. et al

in Investigative Ophthalmology & Visual Science (2001), 42(7), 1574-80

PURPOSE: During an ethylnitrosourea (ENU) mutagenesis screen, mice were tested for the occurrence of dominant cataracts. One particular mutant was found that caused progressive opacity and was referred to ... [more ▼]

PURPOSE: During an ethylnitrosourea (ENU) mutagenesis screen, mice were tested for the occurrence of dominant cataracts. One particular mutant was found that caused progressive opacity and was referred to as Aey2. The purpose of the study was to provide a morphologic description, to map the mutant gene, and to characterize the underlying molecular lesion. METHODS: Isolated lenses were photographed, and histologic sections of the eye were analyzed according to standard procedures. Linkage analysis was performed using a set of microsatellite markers covering all autosomal chromosomes. cDNA from candidate genes was amplified after reverse transcription of lens mRNA. RESULTS: The cortical opacification visible at eye opening progressed to an anterior suture cataract and reached its final phenotype as total opacity at 8 weeks of age. There was no obvious difference between heterozygous and homozygous mutants. The mutation was mapped to chromosome 5 proximal to the marker D5Mit138 (8.7 +/- 4.2 centimorgan [cM]) and distal to D5Mit15 (12.8 +/- 5.4 cM). No recombinations were observed to the markers D5Mit10 and D5Mit25. This position makes the genes within the betaA4/betaB-crystallin gene cluster excellent candidate genes. Sequence analysis revealed a mutation of T-->A at position 553 in the Crybb2 gene, leading to an exchange of Val for GLU: It affects the same region of the Crybb2 gene as in the Philly mouse. Correspondingly, the loss of the fourth Greek key motif is to be expected. CONCLUSIONS: The Aey2 mutant represents the second allele of Crybb2 in mice. Because an increasing number of beta- and gamma-crystallin mutations have been reported, a detailed phenotype-genotype correlation will allow a clearer functional understanding of beta- and gamma-crystallins. [less ▲]

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See detailEthylnitrosourea-induced mutation in mice leads to the expression of a novel protein in the eye and to dominant cataracts.
Graw, J.; Klopp, N.; Loster, J. et al

in Genetics (2001), 157(3), 1313-20

A novel ENU-induced mutation in the mouse leading to a nuclear and zonular opacity of the eye lens (Aey1) was mapped to chromosome 1 between the markers D1Mit303 and D1Mit332. On the basis of the ... [more ▼]

A novel ENU-induced mutation in the mouse leading to a nuclear and zonular opacity of the eye lens (Aey1) was mapped to chromosome 1 between the markers D1Mit303 and D1Mit332. On the basis of the chromosomal position, the gamma-crystallin encoding gene cluster (Cryg) and the betaA2-crystallin encoding gene Cryba2 were tested as candidate genes. An A --> T mutation destroys the start codon of the Cryge gene in the mutants; this mutation was confirmed by the absence of a restriction site for NcoI in the corresponding genomic fragment of homozygous mutants. The next in-frame start codon is 129 bp downstream; this predicted truncated gammaE-crystallin consists of 131 amino acids, resulting in a molecular mass of 14 kD. However, another open reading frame was observed just 19 bp downstream of the regular Cryge start codon, resulting in a protein of 119 amino acids and a calculated molecular weight of 13 kD. Western blot analysis using polyclonal antibodies against gamma-crystallins or the novel Aey1-specific protein demonstrated the specific expression of the Aey1 protein in the cataractous lenses only; the truncated form of the gammaE-crystallin could not be detected. Therefore, it is concluded that the novel protein destroys the sensitive cellular structure of the eye lens. [less ▲]

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See detailCharacterization of a new, dominant V124E mutation in the mouse alphaA-crystallin-encoding gene.
Graw, J.; Loster, J.; Soewarto, D. et al

in Investigative Ophthalmology & Visual Science (2001), 42(12), 2909-15

PURPOSE: During an ethylnitrosourea (ENU) mutagenesis screening, mice were tested for the occurrence of dominant cataracts. The purpose of the study was morphologic description, mapping of the mutant gene ... [more ▼]

PURPOSE: During an ethylnitrosourea (ENU) mutagenesis screening, mice were tested for the occurrence of dominant cataracts. The purpose of the study was morphologic description, mapping of the mutant gene, and characterization of the underlying molecular lesion in a particular mutant, Aey7. METHODS: Isolated lenses were photographed and histologic sections of the eye were analyzed according to standard procedures. Linkage analysis was performed with a set of microsatellite markers covering all autosomal chromosomes. cDNA was amplified after reverse transcription of lens mRNA. For PCR, cDNA or genomic DNA was used as a template. RESULTS: Nuclear opacity and posterior suture anomaly were visible at eye opening and progressed to a nuclear and zonular cataract at 2 months of age. The opacity as well as the microphthalmia was more pronounced in the homozygotes than in the heterozygotes. The mutation was mapped to chromosome 17 between the markers D17Mit133 and D17Mit180. This position made the alphaA-crystallin-encoding gene (Cryaa) an excellent candidate gene. Sequence analysis revealed a mutation of a T to an A at position 371 in the Cryaa cDNA. The mutation was confirmed by an additional MnlI restriction site in the genomic DNA of homozygous mutants leading to replacement of Val with Glu at codon 124 affecting the C-terminal region of the alphaA-crystallin. CONCLUSIONS: The Aey7 mutant represents the first dominant mouse cataract mutation affecting the Cryaa gene. The mutation leads to progressive opacification of the lens. Compared with the beta- and gamma-crystallin-encoding genes, mutations in the alpha-crystallin-encoding genes are rare. [less ▲]

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See detailCharacterization of a mutation in the lens-specific MP70 encoding gene of the mouse leading to a dominant cataract.
Graw, J.; Loster, J.; Soewarto, D. et al

in Experimental Eye Research (2001), 73(6), 867-76

During an ethylnitrosourea mutagenesis screen, Aey5, a new mouse mutation exhibiting an autosomal dominant congenital cataract was isolated. The cataractous phenotype is visible at the eye opening and ... [more ▼]

During an ethylnitrosourea mutagenesis screen, Aey5, a new mouse mutation exhibiting an autosomal dominant congenital cataract was isolated. The cataractous phenotype is visible at the eye opening and progresses to a nuclear and zonular cataract at 2 months of age with no difference in onset or severity between heterozygous and homozygous mutants. Histological analysis revealed that fiber cell differentiation continues at the lens bow region, but the cell nuclei do not degrade normally and remain in the deeper cortex. Further, the lens nucleus has clefts of various sizes while the remainder of the eye was morphologically normal. The mutation was mapped to chromosome 3 between the markers D3Mit101 and D3Mit77 near the connexin encoding genes Gja5 and Gja8. Sequence analysis revealed no differences in the Gja5 gene, but identified a T-->C mutation at position 191 in the Gja8 gene, which was confirmed by an additional Mva 12691 restriction site in the genomic DNA of homozygous mutants. This mutation results in Val-->Ala substitution at codon 64 of connexin50 (Cx50) also known as lens membrane protein 70 (MP70). Aey5 represents the second dominant mouse cataract mutant affecting Cx50, a membrane protein preferentially expressed in the lens. Since both mutations affect similar regions in the first extracellular domain this region appears to be critically important for its function in lens transparency. [less ▲]

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See detailGenome-wide, large-scale production of mutant mice by ENU mutagenesis.
Hrabe de Angelis, M. H.; Flaswinkel, H.; Fuchs, H. et al

in Nature Genetics (2000), 25(4), 444-7

In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model ... [more ▼]

In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations. In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper, leads to a significant increase in the number of mouse models available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html). [less ▲]

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See detailScreening for dysmorphological abnormalities--a powerful tool to isolate new mouse mutants.
Fuchs, H.; Schughart, K.; Wolf, E. et al

in Mammalian Genome : Official Journal of the International Mammalian Genome Society (2000), 11(7), 528-30

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See detailMutation in the betaA3/A1-crystallin encoding gene Cryba1 causes a dominant cataract in the mouse.
Graw, J.; Jung, M.; Loster, J. et al

in Genomics (1999), 62(1), 67-73

During the mouse ENU mutagenesis screen, mice were tested for the occurrence of dominant cataracts. One particular mutant was discovered as a progressive opacity (Po). Heterozygotes show opacification of ... [more ▼]

During the mouse ENU mutagenesis screen, mice were tested for the occurrence of dominant cataracts. One particular mutant was discovered as a progressive opacity (Po). Heterozygotes show opacification of a superficial layer of the fetal nucleus, which progresses and finally forms a nuclear opacity. Since the homozygotes have already developed the total cataract at eye opening, the mode of inheritance is semidominant. Linkage analysis was performed using a set of genome-wide microsatellite markers. The mutation was mapped to chromosome 11 distal of the marker D11Mit242 (9.3 +/- 4.4 cM) and proximal to D11Mit36 (2.3 +/- 2.3 cM). This position makes the betaA3/A1-crystallin encoding gene Cryba1 an excellent candidate gene. Mouse Cryba1 was amplified from lens mRNA. Sequence analysis revealed a mutation of a T to an A at the second base of exon 6, leading to an exchange of Trp by Arg. Computer analysis predicts that the fourth Greek key motif of the affected betaA3/A1-crystallin will not be formed. Moreover, the mutation leads also to an additional splicing signal, to the skipping of the first 3 bp of exon 6, and finally to the deletion of the Trp residue. Both types of mRNA are present in the homozygous mutant lenses. The mutation will be referred to as Cryba1(po1). This particular mouse mutation provides an excellent animal model for a human congenital zonular cataract with suture opacities, which is caused by a mutation in the homologous gene. [less ▲]

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See detailTailchaser (Tlc): a new mouse mutation affecting hair bundle differentiation and hair cell survival.
Kiernan, A. E.; Zalzman, M.; Fuchs, H. et al

in Journal of Neurocytology (1999), 28(10-11), 969-85

We have undertaken a phenotypic approach in the mouse to identifying molecules involved in inner ear function by N-ethyl-N-nitrosourea mutagenesis followed by screening for new dominant mutations ... [more ▼]

We have undertaken a phenotypic approach in the mouse to identifying molecules involved in inner ear function by N-ethyl-N-nitrosourea mutagenesis followed by screening for new dominant mutations affecting hearing or balance. The pathology and genetic mapping of the first of these new mutants, tailchaser (Tlc), is described here. Tlc/+ mutants display classic behavioural symptoms of a vestibular dysfunction, including head-shaking and circling. Behavioural testing of ageing mice revealed a gradual deterioration of both hearing and balance function, indicating that the pathology caused by the Tlc mutation is progressive, similar to many dominant nonsyndromic deafnesses in humans. Based on scanning electron microscopy (SEM) studies, Tlc clearly plays a developmental role in the hair cells of the cochlea since the stereocilia bundles fail to form the characteristic V-shape pattern around the time of birth. By young adult stages, Tlc/+ outer hair bundles are grossly disorganised although inner hair bundles appear relatively normal by SEM. Increased compound action potential thresholds revealed that the Tlc/+ cochlear hair cells were not functioning normally in young adults. Similar to inner hair cells, the hair bundles of the vestibular hair cells also do not appear grossly disordered. However, all types of hair cells in the Tlc/+ inner ear eventually degenerate, apparently regardless of the degree of organisation of their hair bundles. We have mapped the Tlc mutation to a 12 cM region of chromosome 2, between D2Mit164 and D2Mit423. Based on the mode of inheritance and map location, Tlc appears to be a novel mouse mutation affecting both hair cell survival and stereocilia bundle development. [less ▲]

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