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GDF5 truncation is the cause of brachypodism in a C57BL/6 mutant mouse identified through ENU genome‐wide mutagenesis.
Author(s) -
Jaw Thomas,
Lin Jessica,
Chang MeiLing,
Tan SinHui,
Kung John T.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb74-d
Subject(s) - genetics , biology , mutant , gene , phenotype , mutagenesis , mutation , genome , candidate gene , allele , positional cloning , genomic dna , point mutation
With the human genome sequenced, the race is on to understand the functions of the 30,000 or so genes. Ethyl‐nitrosourea (ENU) was used to treat C57BL/6 (B6) male mice, followed by a 3‐generation breeding scheme to generate G3 mice that were screened for dysmorphology phenotypes under recessive genetic control. The primary phenotype of one identified mutant was short limbs. Heritability testing revealed an autosomal recessive mode of transmission. Analysis of (B6 mutant x BALB/c)F2 mice by STR (short tandem repeat) mapping indicated linkage between the mutant phenotype and the 150 to 160 Mb region on chromosome 2. DNA sequencing was performed on a number of candidate genes chosen on the basis of relatedness to the control of limb growth/body size. Among the candidate genes, particular attention was focused on Gdf5 because its mutation had previously been reported to cause brachypodism. Genomic DNA sequencing of the Gdf5 gene showed a T to A point mutation, causing a premature termination of GDF5 protein with 377 amino acids instead of the full‐length 495 amino acids. The new Gdf5 allele we have identified causes less truncation than the previously reported Gdf5 mutation and indicates the critical role played by the C‐terminal region of GDF5 in the developmental control of limb formation.