The mouse curly whiskers (cw) mutations are recessive alleles of hephaestin-like 1 (Hephl1)

Abstract

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 cw2J) revealed a distinct defect in Hephl1 (a frame-shifting, single-base-pair insertion) that is specific to cw2J. The results presented strongly suggest that defects in the Hephl1 gene are the molecular basis of the classical, curly-whiskers mutant phenotypes. Keywords: Positional-candidate approach, Meiotic backcross mapping, Hair morphology, Complementation testing, Splice-site mutation, Frameshift mutation