RESUMEN
Please cite this paper as: The mouse frizzy (fr) and rat 'hairless' (fr(CR)) mutations are natural variants of protease serine S1 family member 8 (Prss8). Experimental Dermatology 2010; 19: 527-532. Abstract: We have previously suggested (based on genetic mapping analysis) that the allelic 'fuzzy' and 'hairless' mutations in the rat are likely orthologues of the mouse frizzy mutation (fr). Here, we analysed three large intraspecific backcross panels that segregated for mouse fr to restrict this locus to a 0.6-Mb region that includes fewer than 30 genes. DNA sequencing of one of these candidates known to be expressed in skin, protease serine S1 family member 8 (Prss8), revealed a T to A transversion associated with the fr allele that would result in a valine to aspartate substitution at residue 170 in the gene product. To test whether this missense mutation might be the molecular basis of this frizzy variant, we crossed fr/fr mice with mice that carried a recessive perinatal lethal mutation in Prss8. Hybrid offspring that inherited both fr and the Prss8 null allele displayed abnormal hair and skin, showing that these two mutations are allelic, and suggesting strongly that the T to A mutation in Prss8 is responsible for the mutant frizzy phenotype. Sequence analysis of all Prss8 coding regions in the 'hairless' rat identified a 12-bp deletion in the third exon, indicating that mouse fr and the rat 'hairless' mutations are indeed orthologues. However, this analysis failed to detect any alterations to Prss8 coding sequences in the allelic 'fuzzy' rat variant.
Asunto(s)
Enfermedades del Cabello/genética , Mutación/genética , Serina Endopeptidasas/genética , Animales , Mapeo Cromosómico , Cromosomas de los Mamíferos/genética , Intercambio Genético/genética , Femenino , Prueba de Complementación Genética , Enfermedades del Cabello/patología , Folículo Piloso/patología , Endogamia , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Mutantes , Mutación Missense/genética , Polimorfismo de Nucleótido Simple/genética , Ratas , Ratas sin Pelo , Ratas Endogámicas BN , Ratas Mutantes , Análisis de Secuencia de ADN , Eliminación de Secuencia/genética , Piel/patología , Vibrisas/patologíaRESUMEN
We have previously shown that the rat fuzzy and Charles River 'hairless' mutations are defects in the same gene on rat Chr 1, and are likely orthologues of the frizzy mutation (fr) on mouse Chr 7. To test the hypothesis that these variants could result from defects in Fgfr2, we crossed fr/fr mice (from the inbred FS/EiJ strain) with mice that carry a recessive lethal mutation in Fgfr2. Mice inheriting both mutations were phenotypically normal, indicating that fr is not an allele of Fgfr2. To genetically map fr, we crossed these hybrid mice, or F(1) mice made by crossing FS/EiJ with the wild-type C57BL/6J or BALB/cBy strains, back to the FS/EiJ strain. The resulting 546 backcross progeny were typed for linked markers to position fr centromeric of Fgfr2, between D7Csu5 and D7Mit165; an interval that contains only 2.7 Mb and fewer than 70 genes. Further characterization of regional recombinants for sequence-level polymorphisms should allow sufficient refinement of fr's location to facilitate an eventual molecular assignment for this classical mutation.
