Hairless stripes in cattle implicate TSR2 in early hair follicle formation

Four related cows showed hairless streaks on various parts of the body regardless pigmentation. The affected stripes occurred in a consistent pattern resembling the lines of Blaschko. The observed nonsyndromic alopecia phenotype occurred across three generations of a single family and is compatible with an X-linked monogenic mode of inheritance. Linkage analysis and subsequent whole genome sequencing of one affected female identified two perfectly associated sequence variants in the critical interval on bovine chromosome X. Both variants occur in complete linkage disequilibrium, and were absent in more than 2’700 controls. An ERCC6L missense mutation is predicted to cause an amino acid substitution of a non-conserved residue. A point mutation at the 5'-splice junction of exon 5 of the TSR2, 20S rRNA accumulation, homolog (S. cerevisiae), gene leads to the production of two mutant transcripts which both contain a frame shift and generate a premature stop codon predicted to truncate approximately 25% of the protein. Interestingly, beside the presence of both physiological TSR2 transcripts, the two mutant transcripts were detected in the hairless skin of affected cows only. Immunohistochemistry using an antibody against the N-terminal part of the bovine protein demonstrated a specific expression of the TSR2 protein in skin and hair of affected and control cows as well as in bovine fetal skin and hair. RNA hybridization in situ showed that Tsr2 is expressed in pre and post natal phases of hair follicle development in mice. Mammalian TSR2 proteins are highly conserved and known to be broadly expressed but their precise in vivo functions are poorly understood. Thus, dissecting a naturally occurring mutation in a domestic animal species, we have identified TSR2 as regulator of hair follicle development.