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; Wier, Gerda van der; Bodemer, Christine; Bygum, Anette; Bursztejn, Anne‐Claire; Gaitanis, George; Paradisi, Mauro; Stratigos, Alexander J.; Weibel, Lisa; Deraison, Céline; Hovnanian, Alain

doi:10.1038/jid.2011.366

Cited by 33 publications

(47 citation statements)

References 31 publications

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“…According to Lacroix et al . [10], some deep intronic mutations activating cryptic splicing sites, may not completely abolish the natural splicing sites, allowing low level production of full length protein. This phenomena was observed in the case of mutations c.1820+ 53G>A and c.283-12T>A, and recognized to possibly be linked with a milder phenotype.…”

Section: Discussionmentioning

confidence: 99%

Is c.1431-12G>A A common European mutation of SPINK5? report of a patient with Netherton Syndrome

Śmigiel

Królak‐Olejnik

Śniegórska³

et al. 2016

Balkan Journal of Medical Genetics

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Netherton Syndrome (NS) is a very rare genetic skin disease resulting from defects in the SPINK5 gene (encoding the protease inhibitor lympho-epithelial Kazal type inhibitor 1, LEKTI1). In this report, we provide a detailed clinical description of a Polish patient with two SPINK5 mutations, the novel c.1816_1820+21delinsCT and possibly recurrent c.1431-12G>A. A detailed pathogenesis of Netherton Syndrome, on the basis of literature review, is discussed in the view of current knowledge about the LEKT1 molecular processing and activity.

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Section: Discussionmentioning

confidence: 99%

Is c.1431-12G>A A common European mutation of SPINK5? report of a patient with Netherton Syndrome

Śmigiel

Królak‐Olejnik

Śniegórska³

et al. 2016

Balkan Journal of Medical Genetics

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“…While this work was being considered for publication, Lacroix et al 35 reported the identification of mutation c.891C4T in 10 Mediterranean NS families predominantly of Greek origin and sharing a common SPINK5 haplotype. Our study adds another Mediterranean patient (Sicily) to those by Lacroix et al, thus supporting c.891C4T as the most frequent SPINK5 mutation in Europe.…”

Section: Note Added In Proofmentioning

confidence: 99%

A synonymous mutation in SPINK5 exon 11 causes Netherton syndrome by altering exonic splicing regulatory elements

et al. 2012

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Netherton syndrome (NS) is a rare, life-threatening ichthyosiform syndrome caused by recessive loss-of-function mutations in SPINK5 gene encoding lymphoepithelial Kazal-type-related inhibitor (LEKTI), a serine protease inhibitor expressed in the most differentiated epidermal layers and crucial for skin barrier function. We report the functional characterization of a previously unrecognized synonymous variant, c.891C4T (p.Cys297Cys), identified in the SPINK5 exon 11 of an NS patient. We demonstrated that the c.891C4T mutation is associated with abnormal pre-mRNA splicing and residual LEKTI expression in the patient's keratinocytes. Subsequent minigene splicing assays and in silico predictions confirmed the direct role of the synonymous mutation in inhibiting exon 11 inclusion by a mechanism that involves the activity of exonic regulatory sequences, namely splicing enhancer and silencer. However, this deleterious effect was not complete and a residual amount of normal mRNA and LEKTI protein could be detected, correlating with the relatively mild patient's phenotype. Our study represents the first identification of a disease-causing SPINK5 mutation that alters splicing without affecting canonical splice sites.

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“…lymphoepithelial Kazal-type-related inhibitor) [2]. Brak LEKTI prowadzi do nadmiernej aktywności proteaz serynowych, co powoduje upośledzenie bariery naskórkowej, stan zapalny i ułatwione wnikanie alergenów [3].…”

Section: Wprowadzenieunclassified

“…Retinoidy doustne, stosowane w zaburzeniach keratynizacji, w przypadku zespołu Comèla-Nethertona mogą zaostrzać skazę atopową [16]. Istnieją doniesienia o skutecznej terapii dożylnymi wlewami immunoglobulin [3]. Podejmowano również próby leczenia przy użyciu infliksymabu, UVA, UVB, PUVA -ze zmiennym efektem [16][17][18].…”

Section: Opis Przypadkuunclassified

Comèl-Netherton syndrome –

Błażewicz¹,

Rustowska²,

Wilkowska³

et al. 2014

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StreSzczenieWprowadzenie. Zespół Comèla-Nethertona jest rzadką, dziedziczoną autosomalnie recesywnie genodermatozą charakteryzującą się występowaniem wrodzonej erytrodermii ichtiotycznej, rybiej łuski linijnej okrążającej, obecnością włosów bambusowatych i skazy atopowej. Zespół ten spowodowany jest mutacją w genie SPINK 5, kodującym inhibitor proteazy serynowej LEKTI. Cel pracy. W pracy przedstawiono trudności diagnostyczne i terapeutyczne u pacjenta z rozpoznaniem zespołu Comèla-Nethertona. Opis przypadku. Przedstawiamy przypadek 3-letniego chłopca, u którego od pierwszej doby życia obserwowano uogólnioną erytrodermię ichtiotyczną i rozlane, grubopłatowe złuszczanie naskórka. Diagnostyka różnicowa obejmowała zespół Omenna, atopowe zapalenie skóry, łojotokowe zapalenie skóry oraz niepęcherzową wrodzoną erytrodermię ichtiotyczną. Ostatecznie na podstawie badania mikroskopowego, w którym wykazano obecność włosów bambusowatych, oraz całokształtu obrazu klinicznego rozpoznano zespół Comèla-Nethertona. Wnioski. Ze względu na podobieństwo do innych erytrodermii rozpoznanie zespołu Comèla-Nethertona w pierwszych miesiącach życia stwarza problemy, a u starszych dzieci nawracające infekcje skóry oraz nasilenie skazy atopowej są przyczyną trudności terapeutycznych i wymagają współpracy wielu specjalistów. AbStrActIntroduction. Comèl-Netherton syndrome is a rare autosomal recessive genodermatosis characterized by congenital ichthyosiform erythroderma, ichthyosis linearis circumflexa, trichorrhexis invaginata, and atopic diathesis. Comèl-Netherton syndrome is caused by mutations of the SPINK5 gene, which encodes the serine protease inhibitor LEKTI. Objective. We present diagnostic and therapeutic difficulties in a patient with Comèl-Netherton syndrome. Case report. We present the case of a 3-year-old boy, in whom from the first day of life generalized ichthyosiform erythroderma and diffuse exfoliation of the skin were observed. The differential diagnosis included Omenn syndrome, and atopic and seborrheic dermatitis. Finally, based on the overall clinical picture and microscopic examination of the hair, which showed the presence of bamboo hair, Comèl-Netherton syndrome was diagnosed. Conclusions.Because of similarity to other erythroderma, diagnosis of Comèl-Netherton syndrome in the first months of life creates diagnostic zespół comèla-nethertona -opis przypadku comèl-netherton syndrome -case report izabela błażewicz, Alicja rustowska, Aleksandra Wilkowska, roman J. nowicki Katedra i Klinika Dermatologii, Wenerologii i Alergologii Gdańskiego Uniwersytetu Medycznego

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

Cited by 33 publications

References 31 publications

Is c.1431-12G>A A common European mutation of SPINK5? report of a patient with Netherton Syndrome

Is c.1431-12G>A A common European mutation of SPINK5? report of a patient with Netherton Syndrome

A synonymous mutation in SPINK5 exon 11 causes Netherton syndrome by altering exonic splicing regulatory elements

Comèl-Netherton syndrome –

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