HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families.

Abstract
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.
AuthorsEmmanuelle Bitoun, Stéphane Chavanas, Alan D Irvine, Lorne Lonie, Christine Bodemer, Mauro Paradisi, Dominique Hamel-Teillac, Shin-ichi Ansai, Yoshihiko Mitsuhashi, Alain Taïeb, Yves de Prost, Giovanna Zambruno, John I Harper, Alain Hovnanian
JournalThe Journal of investigative dermatology (J Invest Dermatol) Vol. 118 Issue 2 Pg. 352-61 (Feb 2002) ISSN: 0022-202X [Print] United States
PMID11841556 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carrier Proteins
  • Codon, Nonsense
  • DNA Transposable Elements
  • Proteinase Inhibitory Proteins, Secretory
  • RNA Splice Sites
  • RNA, Messenger
  • SPINK5 protein, human
  • Serine Peptidase Inhibitor Kazal-Type 5
  • Serine Proteinase Inhibitors
Topics
  • Adolescent
  • Adult
  • Carrier Proteins
  • Child
  • Child, Preschool
  • Codon, Nonsense (genetics)
  • Congenital Abnormalities (genetics)
  • DNA Transposable Elements
  • Exons (genetics)
  • Gene Deletion
  • Genome
  • Genotype
  • Hair (abnormalities)
  • Humans
  • Hypersensitivity (genetics)
  • Ichthyosiform Erythroderma, Congenital (genetics)
  • Infant
  • Molecular Sequence Data
  • Mutation (genetics)
  • Polymorphism, Genetic (genetics)
  • Proteinase Inhibitory Proteins, Secretory
  • RNA Splice Sites (genetics)
  • RNA, Messenger (metabolism)
  • Serine Peptidase Inhibitor Kazal-Type 5
  • Serine Proteinase Inhibitors (genetics)
  • Syndrome

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: