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.
authors.affiliation: INSERM U563, Toulouse, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lacroix
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lacaze-Buzy
authors.forename: Laetitia
authors.initials: L
authors.lastname: Furio
authors.forename: Elodie
authors.initials: E
authors.lastname: Tron
authors.forename: Manthoula
authors.initials: M
authors.lastname: Valari
authors.forename: Gerda
authors.initials: G
authors.lastname: Van der Wier
authors.forename: Christine
authors.initials: C
authors.lastname: Bodemer
authors.forename: Anette
authors.initials: A
authors.lastname: Bygum
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Bursztejn
authors.forename: George
authors.initials: G
authors.lastname: Gaitanis
authors.forename: Mauro
authors.initials: M
authors.lastname: Paradisi
authors.forename: Alexander
authors.initials: A
authors.lastname: Stratigos
authors.forename: Lisa
authors.initials: L
authors.lastname: Weibel
authors.forename: Céline
authors.initials: C
authors.lastname: Deraison
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D056770:Netherton Syndrome / Q000175:diagnosis* / Q000235:genetics*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D000074163:Serine Peptidase Inhibitor Kazal-Type 5
chemical_list: D018389:Codon, Nonsense; D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5