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Science 26 April 1996:
Vol. 272. no. 5261, pp. 548 - 551
DOI: 10.1126/science.272.5261.548
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Reports

Altered Growth and Branching Patterns in Synpolydactyly Caused by Mutations in HOXD13

Yasuteru Muragaki, * Stefan Mundlos, *dagger Joseph Upton, Bjorn R. Olsen

Hox genes regulate patterning during limb development. It is believed that they function in the determination of the timing and extent of local growth rates. Here, it is demonstrated that synpolydactyly, an inherited human abnormality of the hands and feet, is caused by expansions of a polyalanine stretch in the amino-terminal region of HOXD13. The homozygous phenotype includes the transformation of metacarpal and metatarsal bones to short carpal- and tarsal-like bones. The mutations identify the polyalanine stretch outside of the DNA binding domain of HOXD13 as a region necessary for proper protein function.

Y. Muragaki, S. Mundlos, B. R. Olsen, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
J. Upton, Department of Surgery, Division of Plastic Surgery, Beth Israel and Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
* These authors are joint first authors.
dagger To whom correspondence should be addressed.

[Data]


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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    PDF »
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A Pattyn, X Morin, H Cremer, C Goridis, and J. Brunet (1997)
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   Abstract »    PDF »
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   Abstract »    PDF »
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   Abstract »    PDF »
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   Abstract »    PDF »
Mouse models of human disease. Part II: recent progress and future directions..
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   PDF »


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