SPINK5(serine protease inhibitor Kazal-type 5),encoding the protease inhibitor LEKTI(lympho-epithelia lKazal-type related inhibitor),is the defective gene in Netherton syndrome(NS)-,a severe inherited keratinizing dis...SPINK5(serine protease inhibitor Kazal-type 5),encoding the protease inhibitor LEKTI(lympho-epithelia lKazal-type related inhibitor),is the defective gene in Netherton syndrome(NS)-,a severe inherited keratinizing disorder.We have recently demonstrated epidermal protease hyperactivity in Spink5-/-mice resulting in desmosomal protein degradation.Herein,we investigated the molecular mechanism underlying the epidermal defect in 15 patients with NS.We demonstrated that,in a majority of patients,desmoglein 1(Dsg1)and desmocollin 1(Dsc1)were dramatically reduced in the upper most living layers of the epidermis.These defects were associated with premature degradation of corneodesmosomes.Stratum corneum tryptic enzyme(SCTE)-like and stratum corneum chymotryptic enzyme(SCCE)-like activities were increased,suggesting that these proteases participate in the premature degradation of corneodesmosomal cadherins.SCTE and SCCE expression was extended to the cell layers where Dsg1 and Dsc1 immunostaining was reduced.In contrast,a subset of six patients with normal epidermal protease activity or residual LEKTI expression displayed apparently normal cadherin expression and less severe disease manifestations.This suggests a degree of correlation between cadherin degradation and clinical severity.This work further supports the implication of premature corneodesmosomal cadherin degradation in the pathogenesis of NS and provides evidence for additional factors playing a role in disease expression.展开更多
Mutations in the SPINK5 gene encoding the serine protease(SP)inhibitor,lymphoepithelial-Kazal-type 5 inhibitor(LEKTI),cause Netherton syndrome(NS),a life-threat-ening disease,owing to proteolysis of the stratum corneu...Mutations in the SPINK5 gene encoding the serine protease(SP)inhibitor,lymphoepithelial-Kazal-type 5 inhibitor(LEKTI),cause Netherton syndrome(NS),a life-threat-ening disease,owing to proteolysis of the stratum corneum(SC).We assessed here the basis for phenotypic variations in nine patients with “mild”,“moderate”,and “severe”NS.The magnitude of SP activation correlated with both the barrier defect and clinical severity,and inversely with residual LEKTI expression.LEKTI co-localizes within the SC with kallikreins 5 and 7 and inhibits both SP.The permeability barrier abnormality in NS was further linked to SC thinning and proteolysis of two lipid hydrolases(β-glucocerebrosidase and acidic sphingomyelinase),with resultant disorganization of extracellular lamellar membranes.SC attenuation correlated with phenotype-dependent,SP activation,and loss of corneodesmosomes,owing to desmoglein(DSG)1 and desmocollin(DSC)1 degradation.Although excess SP activity extended into the nucleated layers in NS,degrading desmosomal mid-line structures with loss of DSG1/DSC1,the integrity of the nucleated epidermis appears to be maintained by compensatory upregulation of DSG3/DSC3.Maintenance of sufficient permeability barrier function for survival correlated with a compensatory acceleration of lamellar body secretion,providing a partial permeability barrier in NS.These studies provide a mechanistic basis for phenotypic variations in NS,and describe compensatory mechanisms that permit survival of NS patients in the face of unrelenting SP attack.展开更多
文摘SPINK5(serine protease inhibitor Kazal-type 5),encoding the protease inhibitor LEKTI(lympho-epithelia lKazal-type related inhibitor),is the defective gene in Netherton syndrome(NS)-,a severe inherited keratinizing disorder.We have recently demonstrated epidermal protease hyperactivity in Spink5-/-mice resulting in desmosomal protein degradation.Herein,we investigated the molecular mechanism underlying the epidermal defect in 15 patients with NS.We demonstrated that,in a majority of patients,desmoglein 1(Dsg1)and desmocollin 1(Dsc1)were dramatically reduced in the upper most living layers of the epidermis.These defects were associated with premature degradation of corneodesmosomes.Stratum corneum tryptic enzyme(SCTE)-like and stratum corneum chymotryptic enzyme(SCCE)-like activities were increased,suggesting that these proteases participate in the premature degradation of corneodesmosomal cadherins.SCTE and SCCE expression was extended to the cell layers where Dsg1 and Dsc1 immunostaining was reduced.In contrast,a subset of six patients with normal epidermal protease activity or residual LEKTI expression displayed apparently normal cadherin expression and less severe disease manifestations.This suggests a degree of correlation between cadherin degradation and clinical severity.This work further supports the implication of premature corneodesmosomal cadherin degradation in the pathogenesis of NS and provides evidence for additional factors playing a role in disease expression.
文摘Mutations in the SPINK5 gene encoding the serine protease(SP)inhibitor,lymphoepithelial-Kazal-type 5 inhibitor(LEKTI),cause Netherton syndrome(NS),a life-threat-ening disease,owing to proteolysis of the stratum corneum(SC).We assessed here the basis for phenotypic variations in nine patients with “mild”,“moderate”,and “severe”NS.The magnitude of SP activation correlated with both the barrier defect and clinical severity,and inversely with residual LEKTI expression.LEKTI co-localizes within the SC with kallikreins 5 and 7 and inhibits both SP.The permeability barrier abnormality in NS was further linked to SC thinning and proteolysis of two lipid hydrolases(β-glucocerebrosidase and acidic sphingomyelinase),with resultant disorganization of extracellular lamellar membranes.SC attenuation correlated with phenotype-dependent,SP activation,and loss of corneodesmosomes,owing to desmoglein(DSG)1 and desmocollin(DSC)1 degradation.Although excess SP activity extended into the nucleated layers in NS,degrading desmosomal mid-line structures with loss of DSG1/DSC1,the integrity of the nucleated epidermis appears to be maintained by compensatory upregulation of DSG3/DSC3.Maintenance of sufficient permeability barrier function for survival correlated with a compensatory acceleration of lamellar body secretion,providing a partial permeability barrier in NS.These studies provide a mechanistic basis for phenotypic variations in NS,and describe compensatory mechanisms that permit survival of NS patients in the face of unrelenting SP attack.
