title: Hairless Streaks in Cattle Implicate TSR2 in Early Hair Follicle Formation.
abstract: Four related cows showed hairless streaks on various parts of the body with no correlation to the pigmentation pattern. The stripes occurred in a consistent pattern resembling the lines of Blaschko. The non-syndromic hairlessness phenotype observed occurred across three generations of a single family and was compatible with an X-linked mode of inheritance. Linkage analysis and subsequent whole genome sequencing of one affected female identified two perfectly associated non-synonymous sequence variants in the critical interval on bovine chromosome X. Both variants occurred in complete linkage disequilibrium and were absent in more than 3900 controls. An ERCC6L missense mutation was predicted to cause an amino acid substitution of a non-conserved residue. Analysis in mice showed no specific Ercc6l expression pattern related to hair follicle development and therefore ERCC6L was not considered as causative gene. A point mutation at the 5'-splice junction of exon 5 of the TSR2, 20S rRNA accumulation, homolog (S. cerevisiae), gene led to the production of two mutant transcripts, both of which contain a frameshift and generate a premature stop codon predicted to truncate approximately 25% of the protein. Interestingly, in addition to the presence of both physiological TSR2 transcripts, the two mutant transcripts were predominantly detected in the hairless skin of the affected cows. Immunohistochemistry, using an antibody against the N-terminal part of the bovine protein demonstrated the specific expression of the TSR2 protein in the skin and the hair of the affected and the control cows as well as in bovine fetal skin and hair. The RNA hybridization in situ showed that Tsr2 was expressed in pre- and post-natal phases of hair follicle development in mice. Mammalian TSR2 proteins are highly conserved and are known to be broadly expressed, but their precise in vivo functions are poorly understood. Thus, by dissecting a naturally occurring mutation in a domestic animal species, we identified TSR2 as a regulator of hair follicle development.
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland; DermFocus, University of Bern, Bern, Switzerland.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Murgiano
authors.affiliation: Developmental Biology Program, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Vera
authors.initials: V
authors.lastname: Shirokova
authors.affiliation: DermFocus, University of Bern, Bern, Switzerland; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Monika Maria
authors.initials: MM
authors.lastname: Welle
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland; DermFocus, University of Bern, Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Division of Neurological Sciences, DCR-VPH, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Plattet
authors.affiliation: Division of Neurological Sciences, DCR-VPH, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Oevermann
authors.affiliation: Clinic for Reproductive Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
authors.forename: Aldona
authors.initials: A
authors.lastname: Pienkowska-Schelling
authors.affiliation: Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell'Emilia, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Gallo
authors.affiliation: Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell'Emilia, Italy.
authors.forename: Arcangelo
authors.initials: A
authors.lastname: Gentile
authors.affiliation: Developmental Biology Program, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Mikkola
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland; DermFocus, University of Bern, Bern, Switzerland.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001483:Base Sequence; D002417:Cattle; D002874:Chromosome Mapping; D018389:Codon, Nonsense / Q000235:genetics*; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics; D016678:Genome / Q000235:genetics; D018859:Hair Follicle / Q000196:embryology*; D015810:Linkage Disequilibrium / Q000235:genetics; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D051017:Apoptosis Regulatory Proteins; D018389:Codon, Nonsense