Netherton syndrome is a severe autosomal recessive skin disorder characterized 
by congenital erythroderma, a specific hair-shaft abnormality, and atopic 
manifestations with high IgE levels. Recently, we identified SPINK5, which 
encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the 
defective gene in Netherton syndrome. Here we describe the intron-exon 
organization of the gene and characterize the SPINK5 mutations in patients from 
21 families of different geographic origin, using denaturing high performance 
liquid chromatography and direct sequencing. We identified 18 mutations, of 
which 13 were novel and seven (39%) were recurrent. The majority of the 
mutations were clustered between exons 1-8 and exons 21-26. They comprised four 
nonsense mutations (22%), eight frameshift insertions or deletions (44%), and 
six splice-site defects (33%). All mutations predict the formation of premature 
termination codons. Northern blot analysis showed variable reduction of SPINK5 
mutant transcript levels, suggesting variable efficiency of nonsense-mediated 
mRNA decay. Seven patients were homozygotes, eight were compound heterozygotes, 
and five were heterozygotes with only one identifiable SPINK5 mutation. Five 
mutations, one of which resulted in perinatal lethal disease in three families, 
were associated with certain ethnic groups. We also describe 45 intragenic 
polymorphisms in the patients studied. The clinical features of erythroderma, 
trichorrhexis invaginata, and atopic manifestations were present in the majority 
of affected individuals and ichthyosis linearis circumflexa was seen in 12 out 
of 24 patients. Interfamilial and intrafamilial variation in disease severity 
was observed, with no clear correlation between mutations and phenotype, 
suggesting that the degree of severity may be affected by other factors.