The mouse frizzy (fr) and rat ‘hairless’ (fr^CR) mutations are natural variants of protease serine S1 family member 8 (Prss8)

Abstract

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.

Activity and inhibition of prostasin and matriptase on apical and basolateral surfaces of human airway epithelial cells

“…On the other hand, prostasin may activate matriptase in addition to the converse (7), reinforcing the concept that fates and activity of the two enzymes are intertwined. More recently, prostasin catalytic domain mutations were linked to defects in hair and skin development in established strains of mice and rats (28), and skin overexpression caused inflammation and ichthyosis (15). Selective deletion of mouse Prss8 in distal airway epithelial cells reduces alveolar fluid clearance and ENaC-mediated Na ϩ absorption (26), which is consistent with mounting in vitro evidence that prostasin regulates epithelial Na ϩ transport.…”

“…The finding in this work that a sizable pool of active prostasin localizes to the basolateral surface, which is thought to lack ENaC, raises the possibility of targets and roles for prostasin apart from activating ENaC. Roles for prostasin in epithelial monolayer preservation and function not clearly related to regulation of ENaC have been predicted by several studies of engineered and naturally occurring prostasin variants in cultured cells and rodent models of epithelial function (15,19,28,35).…”

The Membrane-anchored Serine Protease Prostasin (CAP1/PRSS8) Supports Epidermal Development and Postnatal Homeostasis Independent of Its Enzymatic Activity

“…CatϪ/CatϪ mice is quite similar to the phenotype observed in both matriptase hypomorphic mice (23) and in the spontaneous mutant mouse strain, frizzy (24). The latter mouse strain carries a point mutation in the Prss8 gene (Prss8 fr/fr ) that results in a non-conservative V170D amino acid substitution in the prostasin protein.…”

The Protease Inhibitor HAI-2, but Not HAI-1, Regulates Matriptase Activation and Shedding through Prostasin

“…A potential caveat of the above experiment, therefore, was that residual HAI-1 could be expressed at levels that eluded detection by Western blot or by immunofluorescence, but were sufficient to allow for appropriate transport to the epithelial cell surface. To examine this possibility, our second approach was to investigate matriptase expression and subcellular localization in intestinal tissues of mice in which complete HAI-1 deficiency was compensated by a hypomorphic mutation in the prostasin gene (Spint1 Ϫ/Ϫ ;Prss8 fr/fr mice) using HAI-1-sufficient prostasin hypomorphic (Spint1 ϩ/ϩ ; Prss8 fr/fr ) littermates as controls (28,47). Again, intestinal matriptase protein expression levels were unaffected by the absence of HAI-1, as determined by Western blot (example in Fig.…”