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, Bruce Alan Buehler, Margharita Larralde de Luna, Mary L. Williams, Bruce Buehler, Elaine C. Siegfried, Lionel Van Maldergem, Sherri J. Bale, Alain Hovnanian

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

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
Volume117
Issue number2
DOIs
StatePublished - Jan 1 2001

Fingerprint

Netherton Syndrome
Prenatal Diagnosis
Exons
Nucleotides
Mutation
Serine Proteinase Inhibitors
Ports and harbors
Immunoglobulin E
Electrolytes
Genes
Tissue
Defects
DNA
Testing
Heteroduplex Analysis
Ichthyosis
Failure to Thrive
Temperature
Lymphoid Tissue
DNA Sequence Analysis

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome : Implications for mutation detection and first case of prenatal diagnosis. / Sprecher, Eli; Amin, Shivan; Nielsen, Karl; Pfendner, Ellen; Uitto, Jouni; Richard, Gabriele; Chavanas, Stephane; Digiovanna, John J.; Prendiville, Julie S.; Silverman, Robert; Esterly, Nancy B.; Esterly, Mary K.; Buehler, Bruce Alan; de Luna, Margharita Larralde; Williams, Mary L.; Buehler, Bruce; Siegfried, Elaine C.; Van Maldergem, Lionel; Bale, Sherri J.; Hovnanian, Alain.

In: Journal of Investigative Dermatology, Vol. 117, No. 2, 01.01.2001, p. 179-187.

Research output: Contribution to journalArticle

Sprecher, E, Amin, S, Nielsen, K, Pfendner, E, Uitto, J, Richard, G, Chavanas, S, Digiovanna, JJ, Prendiville, JS, Silverman, R, Esterly, NB, Esterly, MK, Buehler, BA, de Luna, ML, Williams, ML, Buehler, B, Siegfried, EC, Van Maldergem, L, Bale, SJ & Hovnanian, A 2001, 'The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: Implications for mutation detection and first case of prenatal diagnosis', Journal of Investigative Dermatology, vol. 117, no. 2, pp. 179-187. https://doi.org/10.1046/j.1523-1747.2001.01389.x
Sprecher, Eli ; Amin, Shivan ; Nielsen, Karl ; Pfendner, Ellen ; Uitto, Jouni ; Richard, Gabriele ; Chavanas, Stephane ; Digiovanna, John J. ; Prendiville, Julie S. ; Silverman, Robert ; Esterly, Nancy B. ; Esterly, Mary K. ; Buehler, Bruce Alan ; de Luna, Margharita Larralde ; Williams, Mary L. ; Buehler, Bruce ; Siegfried, Elaine C. ; Van Maldergem, Lionel ; Bale, Sherri J. ; Hovnanian, Alain. / The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome : Implications for mutation detection and first case of prenatal diagnosis. In: Journal of Investigative Dermatology. 2001 ; Vol. 117, No. 2. pp. 179-187.
@article{efef1228ee4f484b81d4a25bf8f0fd2b,
title = "The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: Implications for mutation detection and first case of prenatal diagnosis",
abstract = "The Com{\`e}l-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 Com{\`e}l- Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Com{\`e}l-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Com{\`e}l-Netherton syndrome across families of different origins. The Com{\`e}l-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 Com{\`e}l-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 Com{\`e}l-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 Com{\`e}l-Netherton syndrome.",
keywords = "Atopic dermatitis, Congenital recessive ichthyosis, Hair abnormalities, Linkage analysis, Serine proteinase inhibitors",
author = "Eli Sprecher and Shivan Amin and Karl Nielsen and Ellen Pfendner and Jouni Uitto and Gabriele Richard and Stephane Chavanas and Digiovanna, {John J.} and Prendiville, {Julie S.} and Robert Silverman and Esterly, {Nancy B.} and Esterly, {Mary K.} and Buehler, {Bruce Alan} and {de Luna}, {Margharita Larralde} and Williams, {Mary L.} and Bruce Buehler and Siegfried, {Elaine C.} and {Van Maldergem}, Lionel and Bale, {Sherri J.} and Alain Hovnanian",
year = "2001",
month = "1",
day = "1",
doi = "10.1046/j.1523-1747.2001.01389.x",
language = "English (US)",
volume = "117",
pages = "179--187",
journal = "Journal of Investigative Dermatology",
issn = "0022-202X",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome

T2 - Implications for mutation detection and first case of prenatal diagnosis

AU - Sprecher, Eli

AU - Amin, Shivan

AU - Nielsen, Karl

AU - Pfendner, Ellen

AU - Uitto, Jouni

AU - Richard, Gabriele

AU - Chavanas, Stephane

AU - Digiovanna, John J.

AU - Prendiville, Julie S.

AU - Silverman, Robert

AU - Esterly, Nancy B.

AU - Esterly, Mary K.

AU - Buehler, Bruce Alan

AU - de Luna, Margharita Larralde

AU - Williams, Mary L.

AU - Buehler, Bruce

AU - Siegfried, Elaine C.

AU - Van Maldergem, Lionel

AU - Bale, Sherri J.

AU - Hovnanian, Alain

PY - 2001/1/1

Y1 - 2001/1/1

N2 - 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.

AB - 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.

KW - Atopic dermatitis

KW - Congenital recessive ichthyosis

KW - Hair abnormalities

KW - Linkage analysis

KW - Serine proteinase inhibitors

UR - http://www.scopus.com/inward/record.url?scp=0035723116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035723116&partnerID=8YFLogxK

U2 - 10.1046/j.1523-1747.2001.01389.x

DO - 10.1046/j.1523-1747.2001.01389.x

M3 - Article

VL - 117

SP - 179

EP - 187

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 2

ER -