Clinical Expression and New SPINK5 Splicing Defects in Netherton Syndrome: Unmasking a Frequent Founder Synonymous Mutation and Unconventional Intronic Mutations

Matthieu Lacroix, Laetitia Lacaze-Buzy, Laetitia Furio, Elodie Tron, Manthoula Valari, Gerda Van der Wier, Christine Bodemer, Anette Bygum, Anne-Claire Bursztejn, George Gaitanis, Mauro Paradisi, Alexander Stratigos, Lisa Weibel, Céline Deraison, Alain Hovnanian

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Netherton syndrome (NS) is a severe skin disease caused by loss-of-function mutations in SPINK5 (serine protease inhibitor Kazal-type 5) encoding the serine protease inhibitor LEKTI (lympho-epithelial Kazal type-related inhibitor). Here, we disclose new SPINK5 defects in 12 patients, who presented a clinical triad suggestive of NS with variations in inter- and intra-familial disease expression. We identified a new and frequent synonymous mutation c.891C>T (p.Cys297Cys) in exon 11 of the 12 NS patients. This mutation disrupts an exonic splicing enhancer sequence and causes out-of-frame skipping of exon 11. Haplotype analysis indicates that this mutation is a founder mutation in Greece. Two other new deep intronic mutations, c.283-12T>A in intron 4 and c.1820+53G>A in intron 19, induced partial intronic sequence retention. A new nonsense c.2557C>T (p.Arg853X) mutation was also identified. All mutations led to a premature termination codon resulting in no detectable LEKTI on skin sections. Two patients with deep intronic mutations showed residual LEKTI fragments in cultured keratinocytes. These fragments retained some functional activity, and could therefore, together with other determinants, contribute to modulate the disease phenotype. This new founder mutation, the most frequent mutation described in European populations so far, and these unusual intronic mutations, widen the clinical and molecular spectrum of NS and offer new diagnostic perspectives for NS patients.Journal of Investigative Dermatology advance online publication, 17 November 2011; doi:10.1038/jid.2011.366.
OriginalsprogEngelsk
TidsskriftJournal of Investigative Dermatology
Vol/bind132
Sider (fra-til)575-582
ISSN0022-202X
DOI
StatusUdgivet - 2012

Fingeraftryk

Netherton Syndrome
Serine Proteinase Inhibitors
Introns
Defects
Mutation
Exons
Skin
Dermatology
Silent Mutation
Nonsense Codon
Greece
Keratinocytes
Skin Diseases
Haplotypes

Citer dette

Lacroix, Matthieu ; Lacaze-Buzy, Laetitia ; Furio, Laetitia ; Tron, Elodie ; Valari, Manthoula ; Van der Wier, Gerda ; Bodemer, Christine ; Bygum, Anette ; Bursztejn, Anne-Claire ; Gaitanis, George ; Paradisi, Mauro ; Stratigos, Alexander ; Weibel, Lisa ; Deraison, Céline ; Hovnanian, Alain. / Clinical Expression and New SPINK5 Splicing Defects in Netherton Syndrome: Unmasking a Frequent Founder Synonymous Mutation and Unconventional Intronic Mutations. I: Journal of Investigative Dermatology. 2012 ; Bind 132. s. 575-582.
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title = "Clinical Expression and New SPINK5 Splicing Defects in Netherton Syndrome: Unmasking a Frequent Founder Synonymous Mutation and Unconventional Intronic Mutations",
abstract = "Netherton syndrome (NS) is a severe skin disease caused by loss-of-function mutations in SPINK5 (serine protease inhibitor Kazal-type 5) encoding the serine protease inhibitor LEKTI (lympho-epithelial Kazal type-related inhibitor). Here, we disclose new SPINK5 defects in 12 patients, who presented a clinical triad suggestive of NS with variations in inter- and intra-familial disease expression. We identified a new and frequent synonymous mutation c.891C>T (p.Cys297Cys) in exon 11 of the 12 NS patients. This mutation disrupts an exonic splicing enhancer sequence and causes out-of-frame skipping of exon 11. Haplotype analysis indicates that this mutation is a founder mutation in Greece. Two other new deep intronic mutations, c.283-12T>A in intron 4 and c.1820+53G>A in intron 19, induced partial intronic sequence retention. A new nonsense c.2557C>T (p.Arg853X) mutation was also identified. All mutations led to a premature termination codon resulting in no detectable LEKTI on skin sections. Two patients with deep intronic mutations showed residual LEKTI fragments in cultured keratinocytes. These fragments retained some functional activity, and could therefore, together with other determinants, contribute to modulate the disease phenotype. This new founder mutation, the most frequent mutation described in European populations so far, and these unusual intronic mutations, widen the clinical and molecular spectrum of NS and offer new diagnostic perspectives for NS patients.Journal of Investigative Dermatology advance online publication, 17 November 2011; doi:10.1038/jid.2011.366.",
author = "Matthieu Lacroix and Laetitia Lacaze-Buzy and Laetitia Furio and Elodie Tron and Manthoula Valari and {Van der Wier}, Gerda and Christine Bodemer and Anette Bygum and Anne-Claire Bursztejn and George Gaitanis and Mauro Paradisi and Alexander Stratigos and Lisa Weibel and C{\'e}line Deraison and Alain Hovnanian",
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doi = "10.1038/jid.2011.366",
language = "English",
volume = "132",
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Lacroix, M, Lacaze-Buzy, L, Furio, L, Tron, E, Valari, M, Van der Wier, G, Bodemer, C, Bygum, A, Bursztejn, A-C, Gaitanis, G, Paradisi, M, Stratigos, A, Weibel, L, Deraison, C & Hovnanian, A 2012, 'Clinical Expression and New SPINK5 Splicing Defects in Netherton Syndrome: Unmasking a Frequent Founder Synonymous Mutation and Unconventional Intronic Mutations', Journal of Investigative Dermatology, bind 132, s. 575-582. https://doi.org/10.1038/jid.2011.366

Clinical Expression and New SPINK5 Splicing Defects in Netherton Syndrome: Unmasking a Frequent Founder Synonymous Mutation and Unconventional Intronic Mutations. / Lacroix, Matthieu; Lacaze-Buzy, Laetitia; Furio, Laetitia; Tron, Elodie; Valari, Manthoula; Van der Wier, Gerda; Bodemer, Christine; Bygum, Anette; Bursztejn, Anne-Claire; Gaitanis, George; Paradisi, Mauro; Stratigos, Alexander; Weibel, Lisa; Deraison, Céline; Hovnanian, Alain.

I: Journal of Investigative Dermatology, Bind 132, 2012, s. 575-582.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Clinical Expression and New SPINK5 Splicing Defects in Netherton Syndrome: Unmasking a Frequent Founder Synonymous Mutation and Unconventional Intronic Mutations

AU - Lacroix, Matthieu

AU - Lacaze-Buzy, Laetitia

AU - Furio, Laetitia

AU - Tron, Elodie

AU - Valari, Manthoula

AU - Van der Wier, Gerda

AU - Bodemer, Christine

AU - Bygum, Anette

AU - Bursztejn, Anne-Claire

AU - Gaitanis, George

AU - Paradisi, Mauro

AU - Stratigos, Alexander

AU - Weibel, Lisa

AU - Deraison, Céline

AU - Hovnanian, Alain

PY - 2012

Y1 - 2012

N2 - Netherton syndrome (NS) is a severe skin disease caused by loss-of-function mutations in SPINK5 (serine protease inhibitor Kazal-type 5) encoding the serine protease inhibitor LEKTI (lympho-epithelial Kazal type-related inhibitor). Here, we disclose new SPINK5 defects in 12 patients, who presented a clinical triad suggestive of NS with variations in inter- and intra-familial disease expression. We identified a new and frequent synonymous mutation c.891C>T (p.Cys297Cys) in exon 11 of the 12 NS patients. This mutation disrupts an exonic splicing enhancer sequence and causes out-of-frame skipping of exon 11. Haplotype analysis indicates that this mutation is a founder mutation in Greece. Two other new deep intronic mutations, c.283-12T>A in intron 4 and c.1820+53G>A in intron 19, induced partial intronic sequence retention. A new nonsense c.2557C>T (p.Arg853X) mutation was also identified. All mutations led to a premature termination codon resulting in no detectable LEKTI on skin sections. Two patients with deep intronic mutations showed residual LEKTI fragments in cultured keratinocytes. These fragments retained some functional activity, and could therefore, together with other determinants, contribute to modulate the disease phenotype. This new founder mutation, the most frequent mutation described in European populations so far, and these unusual intronic mutations, widen the clinical and molecular spectrum of NS and offer new diagnostic perspectives for NS patients.Journal of Investigative Dermatology advance online publication, 17 November 2011; doi:10.1038/jid.2011.366.

AB - Netherton syndrome (NS) is a severe skin disease caused by loss-of-function mutations in SPINK5 (serine protease inhibitor Kazal-type 5) encoding the serine protease inhibitor LEKTI (lympho-epithelial Kazal type-related inhibitor). Here, we disclose new SPINK5 defects in 12 patients, who presented a clinical triad suggestive of NS with variations in inter- and intra-familial disease expression. We identified a new and frequent synonymous mutation c.891C>T (p.Cys297Cys) in exon 11 of the 12 NS patients. This mutation disrupts an exonic splicing enhancer sequence and causes out-of-frame skipping of exon 11. Haplotype analysis indicates that this mutation is a founder mutation in Greece. Two other new deep intronic mutations, c.283-12T>A in intron 4 and c.1820+53G>A in intron 19, induced partial intronic sequence retention. A new nonsense c.2557C>T (p.Arg853X) mutation was also identified. All mutations led to a premature termination codon resulting in no detectable LEKTI on skin sections. Two patients with deep intronic mutations showed residual LEKTI fragments in cultured keratinocytes. These fragments retained some functional activity, and could therefore, together with other determinants, contribute to modulate the disease phenotype. This new founder mutation, the most frequent mutation described in European populations so far, and these unusual intronic mutations, widen the clinical and molecular spectrum of NS and offer new diagnostic perspectives for NS patients.Journal of Investigative Dermatology advance online publication, 17 November 2011; doi:10.1038/jid.2011.366.

U2 - 10.1038/jid.2011.366

DO - 10.1038/jid.2011.366

M3 - Journal article

C2 - 22089833

VL - 132

SP - 575

EP - 582

JO - The Journal of Investigative Dermatology

JF - The Journal of Investigative Dermatology

SN - 0022-202X

ER -