Netherton syndrome (NS) is a congenital ichthyosiform dermatosis caused by 
serine protease inhibitor Kazal-type 5 (SPINK5) mutations. Tissue kallikreins 
(KLKs) and lymphoepithelial Kazal-type-related inhibitor (LEKTI) (SPINK5 
product) may contribute to the balance of serine proteases/inhibitors in skin 
and influence skin barrier function and desquamation. SPINK5 mutations, causing 
NS, lead to truncated LEKTI; each NS patient possesses LEKTI of a different 
length, depending on the location of mutations. This study aims to elucidate 
genotype/phenotype correlations in Japanese NS patients and to characterize the 
functions of each LEKTI domain. Since we were unable to demonstrate truncated 
proteins in tissue from patients with NS, we used recombinant protein to test 
the hypothesis that the length of LEKTI correlated with protease inhibitory 
activity. Genotype/phenotype correlations were observed with cutaneous severity, 
growth retardation, skin infection, stratum corneum (SC) protease activities, 
and KLK levels in the SC. Predominant inhibition by LEKTI domains against 
overall SC protease activities was trypsin-like (Phe-Ser-Arg-) activity by LEKTI 
domains 6-12, plasmin- and trypsin-like (Pro-Phe-Arg-) activities by domains 
12-15, chymotrypsin-like activity by all domains, and furin-like activity by 
none. KLK levels were significantly elevated in the SC and serum of NS patients. 
These data link LEKTI domain deficiency and clinical manifestations in NS 
patients and pinpoints to possibilities for targeted therapeutic interventions.