Two New Cataract Loci,CcwandTo3,and Further Mapping of theNppandOpjCataracts in the Mouse

Kerscher, Stefan; Glenister, P. H.; Favor, Jack; Mf, Lyon

doi:10.1006/geno.1996.0420

Cited by 22 publications

(21 citation statements)

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“…Mouse bf was mapped previously to 65.0 centimorgans on mouse chromosome 5, although not with high precision (18). To refine localization of the bf gene, we carried out a backcross of C57BL͞6J mice homozygous for bf with mice of the PWK strain and typed 1,167 progeny for recombination events near bf using markers D5Mit188 and D5Mit282, which flank bf proximally and distally, respectively.…”

Section: Resultsmentioning

confidence: 99%

The mouse organellar biogenesis mutant buff results from a mutation inVps33a, a homologue of yeastvps33andDrosophilacarnation

Suzuki

Oiso

Gautam

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

116

136

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In the mouse, more than 16 loci are associated with mutant phenotypes that include defective pigmentation, aberrant targeting of lysosomal enzymes, prolonged bleeding, and immunodeficiency, the result of defective biogenesis of cytoplasmic organelles: melanosomes, lysosomes, and various storage granules. Many of these mouse mutants are homologous to the human HermanskyPudlak syndrome (HPS), Chediak-Higashi syndrome, and Griscelli syndrome. We have mapped and positionally cloned one of these mouse loci, buff (bf), which has a mutant phenotype similar to that of human HPS. Mouse bf results from a mutation in Vps33a and thus is homologous to the yeast vacuolar protein-sorting mutant vps33 and Drosophila carnation (car). This is the first found defect of the class C vacuole͞prevacuole-associated target soluble Nethylmaleimide-sensitive factor attachment protein receptor (t-SNARE) complex in mammals and the first mammalian mutant found that is directly homologous to a vps mutation of yeast. VPS33A thus is a good candidate gene for a previously uncharacterized form of human HPS.H ermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding, and in most cases pulmonary fibrosis result from defects of melanosomes, platelet-dense granules, and lysosomes (1-4). Somewhat similar disorders, Chediak-Higashi and Griscelli syndromes, are additionally associated with severe immunodeficiency (2, 3). Important clues to the pathogenesis of these disorders have come from the mouse, in which Ͼ16 loci have been associated with mutant phenotypes similar to those of human HPS, Chediak-Higashi syndrome, and Griscelli syndrome (5, 6). Several of these genes have been identified recently and in a number of cases have been shown to result in homologous disorders in mice and humans (2-4). Although the functions of many of the corresponding gene products remain unknown, several are involved in various aspects of trafficking proteins to nascent organelles, particularly melanosomes, lysosomes, and cytoplasmic granules. In the yeast, Ͼ65 proteins have been implicated in biogenesis of the cytoplasmic vacuole, including the products of Ͼ40 vacuolar protein-sorting (vps) loci required for trafficking newly synthesized proteins from the late Golgi͞trans-Golgi network to the vacuole (7, 8). It seems likely that at least as many proteins are associated with organellar biogenesis in mammals.We have mapped and positionally cloned the mouse buff (bf ) locus, which is characterized by recessive coat-color hypopigmentation and mild platelet-storage pool deficiency but has little if any effect on lysosomal function. We find that mouse bf results from a missense substitution in Vps33a, a homologue of yeast vps33. The bf mutation results in defective melanosome morphology and melanogenesis both in vivo and in vitro. Expression of wild-type Vps33a in transfected mouse bf-mutant melanocytes complements this aberrant phenotype, whereas expression of bf-mutant Vps33a does not. These results establish murine bf a...

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Section: Resultsmentioning

confidence: 99%

The mouse organellar biogenesis mutant buff results from a mutation inVps33a, a homologue of yeastvps33andDrosophilacarnation

Suzuki

Oiso

Gautam

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

116

136

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“…The total opacity To3 is placed on chromosome 7 (Kerscher et al, 1996). Mice heterozygous or homozygous for the To3 mutation exhibit a total opacity of the lens with a dense cataract.…”

Section: Limmentioning

confidence: 99%

“…The corresponding gene Crygs was mapped to mouse chromosome 16 . The cataract mutation opj (opacity due to poor juntions) (Everett et al, 1994;Kerscher et al, 1996) was mapped close to Crygs. Sequence analysis of Crygs from Opj mice revealed a mutation coding for a key residue of the core of the N-terminal domain of the protein .…”

Section: The γ γ γ γ γ-Crystallinsmentioning

confidence: 99%

“…The Tcm mutation (total cataract with microphthalmia), a cataract with iris dysplasia and coloboma (Zhou et al, 1997) and the Ccw mutation, cataract and curly whiskers (Kerscher et al, 1996), are localized on mouse chromosome 4. The nuclear-posterior polar opacity (Npp) maps to chromosome 5, and Cat5 (previously To2), a total opacity, to chromosome 10 (Everett et al, 1994).…”

Section: Mutants Waiting For Molecular Characterizationmentioning

confidence: 99%

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Congenital hereditary cataracts

Graw¹

2004

Int. J. Dev. Biol.

126

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Congenital cataracts are rare and occur in developed countries with a frequency of 30 cases among 100,000 births with a further 10 cases being diagnosed during childhood. They reflect mainly genetically caused developmental alterations in the lens and surrounding ocular tissues. Even if modern Human Genetics has made large steps forward in the characterization of human hereditary disorders, the underlying developmental processes can only be investigated in model organisms. The mouse is such a good model because of its similarity (as a mammal) and its genetic characterization. This review brings together our genetic and developmental knowledge of congenital, human cataracts with the corresponding mouse models. First, early events will be influenced by genes coding for transcription factors like Pax6, Pitx3, Maf or Sox. If the lens is maturing, mutations affecting the lens membranes (aquaporins/Mip, Lim-2 or connexins) or the structural proteins of the cytosol of the lens fiber cells (the crystallins) become more important. From a genetic point of view it becomes obvious that cataract-causing mutations are not distributed randomly. The discovery of a broad variety of genes important for eye and lens development made much progress in the recent years. Nevertheless, there still remains a long list of mutations to be characterized and functionally investigated both in mouse and man indicating a broad genetic heterogeneity in that which clinicians simply refer to as a "cataract".

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“…The Opj locus was mapped to mouse chromosome 16, 9.5 Ϯ 1.5cM distal to md (mahoganoid) (32,33). ␥S-crystallin (␥S) 1 is a major component of the adult mammalian lens, essentially replacing the expression of other ␥-crystallins (␥A-F), which are expressed from early embryonic development and are major components of the primary lens fibers and the earliest secondary fibers (17, 34 -36).…”

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confidence: 99%

A Temperature-sensitive Mutation of Crygs in the Murine Opj Cataract

Sinha

Wyatt

Sarra

et al. 2001

Journal of Biological Chemistry

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In Opj, an inherited cataract in mice, opacity is associated with a mutation in Crygs, the gene for ␥S-crystallin, the first mutation to be associated with this gene. A single base change causes replacement of Phe-9, a key hydrophobic residue in the core of the N-terminal domain, by serine. Despite this highly non-conservative change, mutant protein folds normally at low temperature. However, it exhibits a marked, concentration-dependent decrease in solubility, associated with loss of secondary structure, at close to physiological temperatures. This is reminiscent of processes thought to occur in human senile cataracts in which normal proteins become altered and aggregate. The Opj cataract is progressive and more severe in Opj/Opj than in Opj/؉. Lens histology shows that whereas fiber cell morphology in Opj/؉ mice is essentially normal, in Opj/Opj, cortical fiber cell morphology and the loss of maturing fiber cell nuclei are both severely disrupted from early stages. This may indicate a loss of function of ␥S-crystallin which would be consistent with ideas that members of the ␤␥-crystallin superfamily may have roles associated with maintenance of cytoarchitecture.

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Two New Cataract Loci,CcwandTo3,and Further Mapping of theNppandOpjCataracts in the Mouse

Cited by 22 publications

References 1 publication

The mouse organellar biogenesis mutant buff results from a mutation inVps33a, a homologue of yeastvps33andDrosophilacarnation

The mouse organellar biogenesis mutant buff results from a mutation inVps33a, a homologue of yeastvps33andDrosophilacarnation

Congenital hereditary cataracts

A Temperature-sensitive Mutation of Crygs in the Murine Opj Cataract

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