The spontaneous, curly whiskers mutation (abbreviated
cw
) generates kinky, brittle vibrissae in homozygous mice. Although
cw
has been mapped to the centromeric end of mouse Chromosome 9, no particular gene has been causally implicated, and this lack of genetic assignment has stymied
cw
's complete molecular and functional analysis. As a foundation for its positional cloning, we have fine-mapped
cw
to a small, 0.57 Mb interval that contains only three skin-expressed genes, including hephaestin-like 1 (
Hephl1
), which encodes a membrane-bound, multi-copper ferroxidase. Sequence analysis of all
Hephl1
coding regions in
cw
/
cw
mutants revealed a single-base-pair substitution that alters
Hephl1
mRNA splicing, and is specific to the
cw
allele, only. Sequence analysis of a second, independent, re-mutation to curly whiskers (that we verified by complementation testing with
cw
and have designated
cw
2J
) revealed a distinct defect in
Hephl1
(a frame-shifting, single-base-pair insertion) that is specific to
cw
2J
. The results presented strongly suggest that defects in the
Hephl1
gene are the molecular basis of the classical, curly-whiskers mutant phenotypes.
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