BACKGROUND: Loss-of-function mutations in the Kazal-type serine protease 
inhibitor, LEKTI, encoded by the SPINK5 gene cause the rare autosomal recessive 
skin disease Netherton syndrome (NS). G1258A polymorphism in SPINK5 may be 
associated with atopic dermatitis, which shares several clinical features with 
NS.
OBJECTIVES: To determine if the phenotype of NS can be caused by a single null 
mutation in SPINK5 combined with the homozygous G1258A polymorphism.
METHODS: We screened mutations in the gene SPINK5 by direct DNA sequencing and 
position cloning and examined the expressions of the SPINK5-encoded protein 
LEKTI and other relevant proteins by immunostaining and immunoblot.
RESULTS: We describe here a patient who was clinically diagnosed with NS and 
carried a single null mutation in SPINK5 combined with the homozygous G1258A 
polymorphism. SPINK5 mRNA was present at normal levels and LEKTI was expressed 
in the epidermis. Nonetheless, the putative downstream LEKTI substrates stratum 
corneum trypsin-like enzyme (SCTE), desmoglein 1 and protein markers of 
keratinocyte differentiation were expressed abnormally, similar to that seen in 
NS if two null mutant alleles are present.
CONCLUSION: This finding indicates that haploinsufficiency of SPINK5 can cause 
the NS phenotype in the presence of one null mutation with homozygous G1258A 
polymorphisms in SPINK5, and this could impair the function of LEKTI and 
therefore acts as a true mutation.