The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: Implications for mutation detection and first case of prenatal diagnosis

Eli Sprecher, Shivan Amin, Karl Nielsen, Ellen Pfendner, Jouni Uitto, Gabriele Richard, Stephane Chavanas, John J. Digiovanna, Julie S. Prendiville, Robert Silverman, Nancy B. Esterly, Mary K. Esterly, Guelig Ed, Margharita Larralde de Luna, Mary L. Williams, Bruce Buehler, Elaine C. Siegfried, Lionel Van Maldergem, Sherri J. Bale, Alain Hovnanian

Research output: Contribution to journalArticlepeer-review

138 Scopus citations


The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl- Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotypephenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform pre-natal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.

Original languageEnglish (US)
Pages (from-to)179-187
Number of pages9
JournalJournal of Investigative Dermatology
Issue number2
StatePublished - Aug 2001


  • Atopic dermatitis
  • Congenital recessive ichthyosis
  • Hair abnormalities
  • Linkage analysis
  • Serine proteinase inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology


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