A new spontaneous mouse mutation of Hoxd13 with a polyalanine expansion and phenotype similar to human synpolydactyly |
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Authors: | Johnson KR; Sweet HO; Donahue LR; Ward-Bailey P; Bronson RT; Davisson MT |
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Institution: | The Jackson Laboratory, Bar Harbor, ME 04609, USA. krj@jax.org |
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Abstract: | Human synpolydactyly (SPD) is an inherited congenital limb malformation
caused by mutations in the HOXD13 gene. Heterozygotes are typically
characterized by 3/4 finger and 4/5 toe syndactyly with associated
duplicated digits; hands and feet of homozygotes are very small because of
a shortening of the phalanges, metacarpal and metatarsal bones. Here we
describe the phenotype and molecular basis of a spontaneous mutation of
Hoxd13 in mice that provides a phenotypically and molecularly accurate
model for human SPD. The new mutation, named synpolydactyly homolog (spdh),
is a 21 bp in-frame duplication within a polyalanine- encoding region at
the 5'-end of the Hoxd13 coding sequence. The duplication expands the
stretch of alanines from 15 to 22; the same type of expansion occurs in
human SPD mutations. spdh/spdh homozygotes exhibit severe malformations of
all four feet, including polydactyly, syndactyly and brachydactylia. The
phenotype of spdh is much more severe than that exhibited by mice with a
genetically engineered, presumably null, disruption of Hoxd13. Thus spdh
probably acts in a dominant-negative manner and will be valuable for
examining interactions with other Hox genes and their protein products
during limb development. Homozygous mice of both sexes also lack preputial
glands and males do not breed; therefore, spdh/spdh mice may also be
valuable in studies of reproductive physiology and behavior.
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