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
Background: Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by ichthyosiform erythroderma, bamboo hair and atopy. The disease is caused by mutations in the SPINK5 gene, which encodes a p...Background: Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by ichthyosiform erythroderma, bamboo hair and atopy. The disease is caused by mutations in the SPINK5 gene, which encodes a putative serine protease inhibitor, LEKTI (lymphoepithelial Kazal- type- related inhibitor). Previous studies have clearly shown a crucial role for LEKTI in skin barrier formation. Objectives: To identify pathogenic mutations in two Japanese siblings with NS, and further to investigate the consequences of the mutations at the protein level. Methods: To screen for mutations in the SPINK5 gene, all of its exons and splice junctions were amplified by polymerase chain reaction and directly sequenced. In addition, immunohistochemical staining of LEKTI, desmoglein (Dsg) 1 and elafin was performed with their specific antibodies. Results: Mutation analysis resulted in the identification of compound heterozygous mutations, Q713X and R790X, in the SPINK5 gene of both patients. The former one is a novel mutation. Immunohistochemical studies in one patient demonstrated a complete absence of LEKTI and a strong expression of elafin in the patient’ s skin. Dsg1 was normally expressed in our patient. Conclusions: In this report, we describe compound heterozygous mutations in the SPINK5 gene in two Japanese siblings with NS. The result of immunohistochemistry shows LEKTI deficiency and upregulation of elafin in the skin of one patient. Furthermore, our data indicate that degradation of Dsg1 does not always occur in NS.展开更多
Background:Netherton syndrome (NS) is a rare autosomal re-cessive condition characterized by ichthyosi form erythroderma, trichorrhexis invaginata and atopi c manifestations. Confirming the diagnosis may be difficult ...Background:Netherton syndrome (NS) is a rare autosomal re-cessive condition characterized by ichthyosi form erythroderma, trichorrhexis invaginata and atopi c manifestations. Confirming the diagnosis may be difficult in the early stages. Mutations in the SPINK5 gene which encodes for the serine protease inhibitor LE KTI are associated with NS. These mutations create premature termination codons which result in absent or abnormal expression of LEKTI in patients with NS. Obje ctives:To investigate the expression of LEKTI in the skin of patients with NS i n comparison with normal controls and patients with other skin conditions, namel y atopic dermatitis, psoriasis and nonbullous ichthyosiform erythroderma. Method s:Immunohistochemistry was performed on skin sections from four patients with N S, four normal controls, four with atopic dermatitis, two with psoriasis and two with nonbullous ichthyosiform erythroderma, using a primary rabbit polyclonal a ntibody against LEKTI. Results:LEKTI was localized to the stratum granulosum in normal skin. All four skin sections from patients with NS showed absent or very reduced staining for LEKTI. Staining in the other disorders showed positive LEK TI expression in varying patterns. Conclusions:NS can be difficult to diagnose especially in the early stage, which can lead to inappropriate treatments partic ularly if it is misdiagnosed as atopic dermatitis. Immunohistochemistry of skin with an antibody against LEKTI is a potentially useful diagnostic test for NS.展开更多
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.
文摘Background: Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by ichthyosiform erythroderma, bamboo hair and atopy. The disease is caused by mutations in the SPINK5 gene, which encodes a putative serine protease inhibitor, LEKTI (lymphoepithelial Kazal- type- related inhibitor). Previous studies have clearly shown a crucial role for LEKTI in skin barrier formation. Objectives: To identify pathogenic mutations in two Japanese siblings with NS, and further to investigate the consequences of the mutations at the protein level. Methods: To screen for mutations in the SPINK5 gene, all of its exons and splice junctions were amplified by polymerase chain reaction and directly sequenced. In addition, immunohistochemical staining of LEKTI, desmoglein (Dsg) 1 and elafin was performed with their specific antibodies. Results: Mutation analysis resulted in the identification of compound heterozygous mutations, Q713X and R790X, in the SPINK5 gene of both patients. The former one is a novel mutation. Immunohistochemical studies in one patient demonstrated a complete absence of LEKTI and a strong expression of elafin in the patient’ s skin. Dsg1 was normally expressed in our patient. Conclusions: In this report, we describe compound heterozygous mutations in the SPINK5 gene in two Japanese siblings with NS. The result of immunohistochemistry shows LEKTI deficiency and upregulation of elafin in the skin of one patient. Furthermore, our data indicate that degradation of Dsg1 does not always occur in NS.
文摘Background:Netherton syndrome (NS) is a rare autosomal re-cessive condition characterized by ichthyosi form erythroderma, trichorrhexis invaginata and atopi c manifestations. Confirming the diagnosis may be difficult in the early stages. Mutations in the SPINK5 gene which encodes for the serine protease inhibitor LE KTI are associated with NS. These mutations create premature termination codons which result in absent or abnormal expression of LEKTI in patients with NS. Obje ctives:To investigate the expression of LEKTI in the skin of patients with NS i n comparison with normal controls and patients with other skin conditions, namel y atopic dermatitis, psoriasis and nonbullous ichthyosiform erythroderma. Method s:Immunohistochemistry was performed on skin sections from four patients with N S, four normal controls, four with atopic dermatitis, two with psoriasis and two with nonbullous ichthyosiform erythroderma, using a primary rabbit polyclonal a ntibody against LEKTI. Results:LEKTI was localized to the stratum granulosum in normal skin. All four skin sections from patients with NS showed absent or very reduced staining for LEKTI. Staining in the other disorders showed positive LEK TI expression in varying patterns. Conclusions:NS can be difficult to diagnose especially in the early stage, which can lead to inappropriate treatments partic ularly if it is misdiagnosed as atopic dermatitis. Immunohistochemistry of skin with an antibody against LEKTI is a potentially useful diagnostic test for NS.
