Correlation between SPINK5 Gene Mutations and Clinical Manifestations in Netherton Syndrome Patients

Komatsu, Naoya; Saijoh, Kiyofumi; Jayakumar, Arumugam; Clayman, Gary L.; Tohyama, Mikiko; Suga, Yasushi; Mizuno, Yuki; Tsukamoto, Katsuhiko; Taniuchi, Katsushige; Takehara, Kazuhiko; Diamandis, Eleftherios P.

doi:10.1038/sj.jid.5701153

Cited by 87 publications

(83 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 Genotype-phenotype correlation in NS is largely incomplete; however, a correlation between the SPINK5 mutation position, LEKTI domain deficiency and disease severity has been suggested. 8,11,12 In our patient, translation of the aberrant transcript deleted of exon 11 is predicted to result in a truncated protein lacking inhibitory domains 5-15. This, combined with the effect of the c.153delT mutation, would be expected to result in a more severe NS phenotype than the one we actually observed in our patient.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 79%

“…5,6 The SPINK5 mutation database in NS comprises 62 different mutations, [7][8][9][10] and the genotype-phenotype correlation suggests that downstream mutations may partly allow for residual expression of functional LEKTI fragments, which results in less severe phenotypes. 11,12 Here we report on functional characterization of the c.891C4T variant identified in the SPINK5 gene in an Italian patient with NS. We use patient keratinocytes, minigene constructs and bioinformatic predictors to demonstrate that this synonymous change (p.Cys 297Cys), despite being distant from the acceptor splice site, induces an incomplete exon skipping by affecting a mechanism underlying splicing regulation.…”

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Section: Genotype-phenotype Correlationmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 95%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Because NS patients with mutations in exons 1-25 of SPINK5, which encode D1-D12 region of LEKTI, present severe phenotypes, mutations at N-terminal and C-terminal regions in SPINK5 may cause severer and milder phenotypes, respectively (8,9). Because p.Arg578X located in D9 region was reported to cause moderate to severe phenotype (6,8), synonymous mutation, c.474G>A, was considered to be responsible for the milder phenotype in our patient.…”

Section: Discussionmentioning

confidence: 92%

“…Because p.Arg578X located in D9 region was reported to cause moderate to severe phenotype (6,8), synonymous mutation, c.474G>A, was considered to be responsible for the milder phenotype in our patient. Our RT-PCR for c.474G>A detected three transcripts, including two out-of-frame transcripts and an in-frame transcript.…”

Section: Discussionmentioning

confidence: 99%

A compound synonymous mutation c.474G>A with p.Arg578X mutation in SPINK5 causes splicing disorder and mild phenotype in Netherton syndrome

Numata

Teye

Krol

et al. 2016

Experimental Dermatology

View full text Add to dashboard Cite

Abbreviations: CHO, Chinese hamster ovary; LEKTI, lymphoepithelial Kazal-type-related inhibitor; NS, Netherton syndrome; SPINK5, serine protease inhibitor Kazal-type 5.Key words: Netherton syndrome -p.Gln158Gln -pathogenicity -SPINK5Accepted for publication 25 February 2016 Background Netherton syndrome (NS; OMIM 256500) is an autosomal recessive disorder caused by mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes lymphoepithelial Kazal-type-related inhibitor (LEKTI) (1). LEKTI consists of 15 domains (D1-D15) and is expressed in epidermis (2). Three LEKTI isoforms exist in human: full-length form with 15 domains (LEKTI FL ), long form carrying additional 30 amino acids between D13 and D14 (LEKTI L ), and short form with first 13 domains (LEKTI S ) (3). Processed fragments of LEKTI inhibit kallikreins, which are desquamation-related enzymes in epidermis (3,4), and lack of LEKTI thereof causes stratum corneum detachment due to hyperactivity of epidermal proteases.Only few studies about synonymous mutation in autosomal recessive congenital ichthyosis have been reported (5). In this report, we describe a synonymous mutation in NS. Questions addressedWhether the synonymous mutation c.474G>A (p.Gln158Gln) in SPINK5 is pathogenic. Experimental design and resultsThe patient was a Japanese male infant born as collodion baby by normal vaginal delivery as the second child of healthy non-consanguineous parents. There was no family history of congenital ichthyosis. At birth, erythroderma and yellowish thick scales were observed on the entire body (Fig. 1a), but serum IgE level was normal. LEKTI did not seem to be expressed (Fig. 1b), when compared to the staining of normal skin (Fig. 1c). However, inadequate preservation of skin tissue made the diagnosis obscure. One month later, erythroderma decreased and ichthyosis linearis circumflexa-like skin lesions appeared on the trunk (Fig. 1d). By these symptoms, diagnosis of NS was suspected. One year later, trichorrhexis invaginata was noted (Fig. 1e), and serum IgE was elevated to 528 U/ml (normal; <173 U/ml). The patient showed mild phenotype at age 2 years.Written informed consents were obtained from the parents and normal volunteers. All studies were performed according to Declaration of Helsinki Principles. Medical Ethics Committee of Kurume University School of Medicine approved this study.Genetic study of genomic DNA from the patient detected two mutations: c.474G>A and c.1732C>T (Fig. 1f). c.1732C>T was a recurrent mutation in exon 19, designated p.Arg578X (GenBank NM_001127698) (6) (Fig. 1f). c.474G>A was an unreported synonymous mutation, designated p.Gln158Gln, which locates at the end of exon 6 (Fig. 1f). c.474G>A and c.1732C>T were found in genomic DNAs from the mother and father, respectively.To confirm the pathogenicity of the synonymous mutation, we examined RNA obtained from the patient skin by RT-PCR from exon 4 to exon 9 region. Control RNA from normal skin showed a single amplified cDNA fragment of 549 bp, which was the no...

show abstract

“…22 We showed that both fragments inhibited rhK5 similarly and established that LEKTI, at least in fragment form, is a potent inhibitor of rhK5 and that this protease may be a target of LEKTI, a physiological inhibitor of multiple serine proteinases, blocks migration and invasion of head and neck squamous cell carcinoma (HNSCC) cells Volume 1 Issue 3 -2014 Arumugam Jayakumar, 1,2 Chandrani Chattopadhyay, 1 Hua-Kang Wu, 1 Katrina Briggs, 1 Ying Henderson, 1 Yaan Kang, LEKTI in human skin. In our later studies we discovered that KLK5, KLK6, KLK13 and KLK14 were potently inhibited by rLEKTI (1)(2)(3)(4)(5)(6), rLEKTI (6-9') and rLEKTI (9)(10)(11)(12). 23,24 We also assessed the basis for phenotypic variations in patients with "mild", "moderate" and "severe" NS.…”

Section: Introductionmentioning

confidence: 99%

LEKTI, A Physiological Inhibitor of Multiple Serine Proteinases, Blocks Migration and Invasion of Head and Neck Squamous Cell Carcinoma (HNSCC) Cells

Jayakumar¹,

Chattopadhyay

Wu³

et al. 2014

MOJPB

Self Cite

View full text Add to dashboard Cite

Correlation between SPINK5 Gene Mutations and Clinical Manifestations in Netherton Syndrome Patients

Cited by 87 publications

References 41 publications

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

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

A compound synonymous mutation c.474G>A with p.Arg578X mutation in SPINK5 causes splicing disorder and mild phenotype in Netherton syndrome

LEKTI, A Physiological Inhibitor of Multiple Serine Proteinases, Blocks Migration and Invasion of Head and Neck Squamous Cell Carcinoma (HNSCC) Cells

Contact Info

Product

Resources

About