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.

The Solution Structure of a Chimeric LEKTI Domain Reveals a Chameleon Sequence

“…All NMR experiments were carried out at 298 K on a commercial Bruker DRX600 spectrometer equipped with a tripleresonance 1 H, 13 (27) with a relaxation delay of 6 s; the evolution time increments in the indirect dimension of the spectra with and without proton saturation by application of a train of 120°high-power pulses for the final 3 s of the relaxation delay were recorded alternately in a single combined experiment.…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…189 In summary, molecular diagnosis is a crucial diagnostic tool and has become in some countries the gold standard for the diagnosis of the ichthyoses and MEDOC in general. It provides a firm basis for genetic counseling of affected individuals and families and permits DNA-based prenatal diagnosis for families at risk, as has been demonstrated in NS, [190][191][192] KPI,[193][194][195] Sjögren-Larsson syndrome, 196 HI, 197,198 and others.…”

Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice

“…It is characterized by ichthyosiform erythroderma, atopic dermatitis, bamboo hair, skin barrier defects, and elevated IgE levels in survivors (Krafchik and Toole 1983;Judge et al 1994). Mutations have been identified in the SPINK5 (serine proteinase inhibitor Kazal type 5) gene of NS patients (Chavanas et al 2000;Sprecher et al 2001;Walley et al 2001;Bitoun et al 2002;Komatsu et al 2002). SPINK5 encodes LEKTI (lympho-epithelial Kazal-type-related inhibitor), which is a putative proteinase inhibitor that contains an N-terminal signal peptide and 15 domains with high internal homology (Magert et al 1999).…”