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 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. Genotype-phenotype 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 prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.
authors.affiliation: Department of Dermatology and Cutaneous Biology and Jefferson Institute of Molecular Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
authors.forename: E
authors.initials: E
authors.lastname: Sprecher
authors.forename: S
authors.initials: S
authors.lastname: Chavanas
authors.forename: J J
authors.initials: JJ
authors.lastname: DiGiovanna
authors.forename: S
authors.initials: S
authors.lastname: Amin
authors.forename: K
authors.initials: K
authors.lastname: Nielsen
authors.forename: J S
authors.initials: JS
authors.lastname: Prendiville
authors.forename: R
authors.initials: R
authors.lastname: Silverman
authors.forename: N B
authors.initials: NB
authors.lastname: Esterly
authors.forename: M K
authors.initials: MK
authors.lastname: Spraker
authors.forename: E
authors.initials: E
authors.lastname: Guelig
authors.forename: M L
authors.initials: ML
authors.lastname: de Luna
authors.forename: M L
authors.initials: ML
authors.lastname: Williams
authors.forename: B
authors.initials: B
authors.lastname: Buehler
authors.forename: E C
authors.initials: EC
authors.lastname: Siegfried
authors.forename: L
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: E
authors.initials: E
authors.lastname: Pfendner
authors.forename: S J
authors.initials: SJ
authors.lastname: Bale
authors.forename: J
authors.initials: J
authors.lastname: Uitto
authors.forename: A
authors.initials: A
authors.lastname: Hovnanian
authors.forename: G
authors.initials: G
authors.lastname: Richard
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D017931:DNA Primers; D003876:Dermatitis, Atopic / Q000235:genetics; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D006197:Hair / Q000002:abnormalities*; D020180:Heteroduplex Analysis; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital / Q000235:genetics*; D007223:Infant; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D011247:Pregnancy; D011296:Prenatal Diagnosis; D053491:Proteinase Inhibitory Proteins, Secretory; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D018389:Codon, Nonsense; D017931:DNA Primers; D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors