Mutations of the serine protease CAP1/Prss8 lead to reduced embryonic viability, skin defects, and decreased ENaC activity.
CAP1/Prss8 is a membrane-bound serine protease involved in the regulation of several different effectors, such as the epithelial sodium channel ENaC, the protease-activated receptor PAR2, the tight junction proteins, and the profilaggrin polypeptide. Recently, the V170D and the G54-P57 deletion mutations within the CAP1/Prss8 gene, identified in mouse frizzy (fr) and rat hairless (fr(CR)) animals, respectively, have been proposed to be responsible for their skin phenotypes. In the present study, we analyzed those mutations, revealing a change in the protein structure, a modification of the glycosylation state, and an overall reduction in the activation of ENaC of the two mutant proteins. In vivo analyses demonstrated that both fr and fr(CR) mutant animals present analogous reduction of embryonic viability, similar histologic aberrations at the level of the skin, and a significant decrease in the activity of ENaC in the distal colon compared with their control littermates. Hairless rats additionally had dehydration defects in skin and intestine and significant reduction in the body weight. In conclusion, we provided molecular and functional evidence that CAP1/Prss8 mutations are accountable for the defects in fr and fr(CR) animals, and we furthermore demonstrate a decreased function of the CAP1/Prss8 mutant proteins. Therefore, fr and fr(CR) animals are suitable models to investigate the consequences of CAP1/Prss8 action on its target proteins in the whole organism.
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Simona
S
Frateschi
Anna
A
Keppner
Sumedha
S
Malsure
Justyna
J
Iwaszkiewicz
Chloé
C
Sergi
Anne-Marie
AM
Merillat
Nicole
N
Fowler-Jaeger
Nadia
N
Randrianarison
Carole
C
Planès
Edith
E
Hummler
D000595:Amino Acid Sequence; D000818:Animals; D001835:Body Weight; D003681:Dehydration / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism* / Q000473:pathology*; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006197:Hair / Q000473:pathology; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D015640:Ion Channel Gating; D051379:Mice; D023421:Models, Animal; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity; D010641:Phenotype; D017434:Protein Structure, Tertiary; D051381:Rats; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000196:embryology* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D040681:Structural Homology, Protein; D014981:Xenopus; D000099271:Prostasin
D053503:Epithelial Sodium Channels; D050505:Mutant Proteins; D012697:Serine Endopeptidases; D000099271:Prostasin