PUBLICATION

Genetic analysis of fin development in zebrafish identifies furin and hemicentin1 as potential novel Fraser Syndrome disease genes

Authors
Carney, T.J., Feitosa, N.M., Sonntag, C., Slanchev, K., Kluger, J., Kiyozumi, D., Gebauer, J.M., Coffin Talbot, J., Kimmel, C.B., Sekiguchi, K., Wagener, R., Schwarz, H., Ingham, P.W., and Hammerschmidt, M.
ID
ZDB-PUB-100427-24
Date
2010
Source
PLoS Genetics   6(4): e1000907 (Journal)
Registered Authors
Carney, Tom, Feitosa, Natalia Martins, Hammerschmidt, Matthias, Ingham, Philip, Kimmel, Charles B., Slanchev, Krasimir, Sonntag, Carmen
Keywords
Embryos, Zebrafish, Blisters, Basement membrane, Phenotypes, Morpholino, Nonsense mutation, Complementary DNA
MeSH Terms
  • Proprotein Convertases/genetics*
  • Proprotein Convertases/metabolism
  • Animals
  • Furin/genetics*
  • Furin/metabolism
  • Mice
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Mutation*
  • Base Sequence
  • Amino Acid Sequence
  • Frasier Syndrome/genetics*
  • Gene Expression Regulation, Developmental
  • Embryo, Nonmammalian/metabolism*
  • Extracellular Matrix Proteins/genetics*
  • Extracellular Matrix Proteins/metabolism
  • Zebrafish/embryology*
  • Molecular Sequence Data
(all 18)
PubMed
20419147 Full text @ PLoS Genet.
Abstract
Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in embryonic fin morphogenesis, which are due to mutations in a Laminin subunit or an Integrin alpha receptor, respectively. The mutants of the second class display characteristic blistering underneath the basement membrane of the fin epidermis. Three of them are due to mutations in zebrafish orthologues of FRAS1, FREM1, or FREM2, large basement membrane protein encoding genes that are mutated in mouse bleb mutants and in human patients suffering from Fraser Syndrome, a rare congenital condition characterized by syndactyly and cryptophthalmos. Fin blistering in a fourth group of zebrafish mutants is caused by mutations in Hemicentin1 (Hmcn1), another large extracellular matrix protein the function of which in vertebrates was hitherto unknown. Our mutant and dose-dependent interaction data suggest a potential involvement of Hmcn1 in Fraser complex-dependent basement membrane anchorage. Furthermore, we present biochemical and genetic data suggesting a role for the proprotein convertase FurinA in zebrafish fin development and cell surface shedding of Fras1 and Frem2, thereby allowing proper localization of the proteins within the basement membrane of forming fins. Finally, we identify the extracellular matrix protein Fibrillin2 as an indispensable interaction partner of Hmcn1. Thus we have defined a series of zebrafish mutants modelling Fraser Syndrome and have identified several implicated novel genes that might help to further elucidate the mechanisms of basement membrane anchorage and of the disease's aetiology. In addition, the novel genes might prove helpful to unravel the molecular nature of thus far unresolved cases of the human disease.
Genes / Markers
Figures
Figure Gallery (14 images) / 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b1048
    Point Mutation
    b1130
      Point Mutation
      fr21
        Point Mutation
        fr22
          Point Mutation
          fr23
            Point Mutation
            ta90
              Point Mutation
              tc17
                Unknown
                tc280b
                  Point Mutation
                  td204e
                    Point Mutation
                    te262d
                      Point Mutation
                      1 - 10 of 14
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                      Human Disease / Model
                      Human Disease Fish Conditions Evidence
                      Fraser syndromeTAS
                      1 - 1 of 1
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                      Sequence Targeting Reagents
                      1 - 10 of 23
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                      Fish
                      Antibodies
                      Name Type Antigen Genes Isotypes Host Organism
                      Ab1-fras1polyclonalRabbit
                      Ab1-tp63monoclonalIgG2aMouse
                      1 - 2 of 2
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                      Orthology
                      No data available
                      Engineered Foreign Genes
                      No data available
                      Mapping
                      Entity Type Entity Symbol Location
                      Featureb1048Chr: 5 Details
                      Featureb1130Chr: 5 Details
                      Featurefr21Chr: 12 Details
                      Featurefr22Chr: 20 Details
                      Featurefr23Chr: 7 Details
                      Featureta90Chr: 10 Details
                      Featuretc17Chr: 23 Details
                      Featuretc280bChr: 7 Details
                      Featurete262dChr: 5 Details
                      Featuretm95bChr: 5 Details
                      1 - 10 of 27
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