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Gene Review

SPINK5  -  serine peptidase inhibitor, Kazal type 5

Homo sapiens

Synonyms: DKFZp686K19184, FLJ21544, FLJ97536, FLJ97596, FLJ99794, ...
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Disease relevance of SPINK5


High impact information on SPINK5

  • We have identified six coding polymorphisms in SPINK5 (Table 1) and found that a Glu420-->Lys variant shows significant association with atopy and AD in two independent panels of families [6].
  • The gene underlying Netherton disease (SPINK5) encodes a 15-domain serine proteinase inhibitor (LEKTI) which is expressed in epithelial and mucosal surfaces and in the thymus [6].
  • Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome [7].
  • Netherton syndrome (NS) is a human autosomal recessive skin disease caused by mutations in the SPINK5 gene, which encodes the putative proteinase inhibitor LEKTI [8].
  • However, adhesion to the human epithelial cell line HeLa S3 did not differ for these two candidal species: specific adhesion was highest for C. albicans at 44.0 +/- 1.8%, and only slightly lower for C. tropicalis at 38.8 +/- 3.6% (P = NS) [9].

Chemical compound and disease context of SPINK5


Biological context of SPINK5

  • 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 [12].
  • Seven patients were homozygotes, eight were compound heterozygotes, and five were heterozygotes with only one identifiable SPINK5 mutation [13].
  • Northern blot analysis showed variable reduction of SPINK5 mutant transcript levels, suggesting variable efficiency of nonsense-mediated mRNA decay [13].
  • We studied the possible association of the SPINK5 gene for the development of atopic diseases by determining the genotypes of five polymorphisms in a Japanese population [14].
  • CONCLUSION: Our results confirm that early truncation mutations of the coding sequence of SPINK5 produce a severe phenotype and that generalized peeling skin is one of the manifestations of NTS [4].

Anatomical context of SPINK5

  • The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues [12].
  • Deletion of the N-terminal signal peptide of pro-LEKTI caused altered distribution of LEKTI from endoplasmic reticulum (ER) to cytoplasm and markedly reduced its stability, consistent with its failure to become secreted into the medium [5].
  • A significant proportion of both PBC patients and controls showed T-cell responses to whole PDC (12 of 24 vs. 24 of 48 SI > 2.5 P = NS) and E1 (15 of 24 vs. 25 of 48 P = NS) [15].
  • Most of the NS3 processed from NS delta 4A was localized in the cytosol fraction and was degraded promptly [16].
  • Insulin-like growth factor I (IGF-I) caused a dose-dependent inhibition of 11betaHSD1 activity in sc [49.7 +/- 15.0% (IGF-I, 100 ng/ml]; P < 0.05 vs. control (100%)] and omental [71.6 +/- 7.5 (IGF-I, 100 ng/ml); P < 0.01 vs. control (100%)] stromal cells, but not in human hepatocytes [101.8 +/- 15.7% (IGF-I, 100 ng/ml); P = NS vs. control (100%)] [17].

Associations of SPINK5 with chemical compounds

  • Coexpression of various KLK and SPINK5 mRNA suggests that their proteins are the candidates to balance and maintain serine protease activities in both the skin and appendages [18].
  • AIMS OF THE STUDY: Development of a high throughput assay to analyse the polymorphism G1258A (Glu420Lys) in exon 14 of the SPINK5 gene followed by the validation using samples of 235 latex-allergic health care workers (HCWs) with (N=63) and without asthma (N=172), and 80 non-atopic controls [19].
  • This calcium-dependent cysteine protease resembles the large subunit of m-calpain but with three unique additional sequences: an N-terminal region (NS), and two insertions (IS1 and IS2) [11].
  • Recurrent disease developed in 34% of patients concurrently treated with cyclosporine and in 28% of those treated with prednisone and azathioprine alone (NS) [20].
  • The cytologic examination of NS, accompanying the nasal challenge with allergen, appears therefore to be a valuable supplementary diagnostic parameter for the LNR and a promising model for further immunologic and clinical studies of the LNR [21].

Regulatory relationships of SPINK5

  • Inhibitors of furin lead to enhanced secretion of unprocessed LEKTI, suggesting that processing was not required for secretion [5].

Other interactions of SPINK5

  • In situ hybridization revealed intense expression of all KLK mRNA studied except KLK12 mRNA in the stratum granulosum of normal epidermis, where SPINK5 mRNA coexisted [18].
  • Collectively, these results suggest that in normal skin the LG system transports and secretes LEKTI earlier than KLK7 and KLK5 preventing premature loss of stratum corneum integrity/cohesion [2].
  • Our study indicates that multiple KLKs may participate in desquamation through cleavage of desmoglein 1 and regulation by LEKTI [22].
  • Recently, we identified SPINK5, which encodes the serine protease inhibitor Kazal-type 5 protein (LEKTI), as the defective gene in Netherton syndrome [13].
  • In addition, in vitro cleavage of the recombinant 145 kDa precursor by furin generated C-terminal fragments of 65 and 68 kDa, further supporting the involvement of furin in LEKTI processing [23].

Analytical, diagnostic and therapeutic context of SPINK5

  • The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis [12].
  • Sequence analyses of SPINK5 in seven NTS patients from five different families allowed us to identify two known and three novel mutations all creating premature termination codons [24].
  • Here we describe the intron-exon organization of the gene and characterize the SPINK5 mutations in patients from 21 families of different geographic origin, using denaturing high performance liquid chromatography and direct sequencing [13].
  • Rapid detection of the SPINK5 polymorphism Glu420Lys by real-time PCR technology [19].
  • The temperatures in the melting analysis of the SPINK5 exon 14 PCR product were characteristic to the probes hybridised to the mutant (AA) at 51.5 degrees C and to the wild-type (GG) at 59.5 degrees C. The fast and reliable mutation detection in the tested samples makes this high-speed method suitable for larger epidemiological studies [19].


  1. The genetics of psoriasis, psoriatic arthritis and atopic dermatitis. Bowcock, A.M., Cookson, W.O. Hum. Mol. Genet. (2004) [Pubmed]
  2. LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum. Ishida-Yamamoto, A., Deraison, C., Bonnart, C., Bitoun, E., Robinson, R., O'Brien, T.J., Wakamatsu, K., Ohtsubo, S., Takahashi, H., Hashimoto, Y., Dopping-Hepenstal, P.J., McGrath, J.A., Iizuka, H., Richard, G., Hovnanian, A. J. Invest. Dermatol. (2005) [Pubmed]
  3. SPINK5: both rare and common skin disease. Norgett, E.E., Kelsell, D.P. Trends in molecular medicine. (2002) [Pubmed]
  4. Netherton syndrome with extensive skin peeling and failure to thrive due to a homozygous frameshift mutation in SPINK5. Geyer, A.S., Ratajczak, P., Pol-Rodriguez, M., Millar, W.S., Garzon, M., Richard, G. Dermatology (Basel) (2005) [Pubmed]
  5. Consequences of C-terminal domains and N-terminal signal peptide deletions on LEKTI secretion, stability, and subcellular distribution. Jayakumar, A., Kang, Y., Henderson, Y., Mitsudo, K., Liu, X., Briggs, K., Wang, M., Frederick, M.J., El-Naggar, A.K., Bebök, Z., Clayman, G.L. Arch. Biochem. Biophys. (2005) [Pubmed]
  6. Gene polymorphism in Netherton and common atopic disease. Walley, A.J., Chavanas, S., Moffatt, M.F., Esnouf, R.M., Ubhi, B., Lawrence, R., Wong, K., Abecasis, G.R., Jones, E.Y., Harper, J.I., Hovnanian, A., Cookson, W.O. Nat. Genet. (2001) [Pubmed]
  7. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Chavanas, S., Bodemer, C., Rochat, A., Hamel-Teillac, D., Ali, M., Irvine, A.D., Bonafé, J.L., Wilkinson, J., Taïeb, A., Barrandon, Y., Harper, J.I., de Prost, Y., Hovnanian, A. Nat. Genet. (2000) [Pubmed]
  8. Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice. Yang, T., Liang, D., Koch, P.J., Hohl, D., Kheradmand, F., Overbeek, P.A. Genes Dev. (2004) [Pubmed]
  9. Distinct mechanisms of epithelial adhesion for Candida albicans and Candida tropicalis. Identification of the participating ligands and development of inhibitory peptides. Bendel, C.M., Hostetter, M.K. J. Clin. Invest. (1993) [Pubmed]
  10. Purification and partial amino acid sequence of proteins from human epidermal keratinocyte conditioned medium. Ahmed, A., Kandola, P., Ziada, G., Parenteau, N. J. Protein Chem. (2001) [Pubmed]
  11. Insertion sequence 1 of muscle-specific calpain, p94, acts as an internal propeptide. Diaz, B.G., Moldoveanu, T., Kuiper, M.J., Campbell, R.L., Davies, P.L. J. Biol. Chem. (2004) [Pubmed]
  12. The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. Sprecher, E., Chavanas, S., DiGiovanna, J.J., Amin, S., Nielsen, K., Prendiville, J.S., Silverman, R., Esterly, N.B., Spraker, M.K., Guelig, E., de Luna, M.L., Williams, M.L., Buehler, B., Siegfried, E.C., Van Maldergem, L., Pfendner, E., Bale, S.J., Uitto, J., Hovnanian, A., Richard, G. J. Invest. Dermatol. (2001) [Pubmed]
  13. Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. Bitoun, E., Chavanas, S., Irvine, A.D., Lonie, L., Bodemer, C., Paradisi, M., Hamel-Teillac, D., Ansai, S., Mitsuhashi, Y., Taïeb, A., de Prost, Y., Zambruno, G., Harper, J.I., Hovnanian, A. J. Invest. Dermatol. (2002) [Pubmed]
  14. Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. Nishio, Y., Noguchi, E., Shibasaki, M., Kamioka, M., Ichikawa, E., Ichikawa, K., Umebayashi, Y., Otsuka, F., Arinami, T. Genes Immun. (2003) [Pubmed]
  15. T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis. Jones, D.E., Palmer, J.M., James, O.F., Yeaman, S.J., Bassendine, M.F., Diamond, A.G. Hepatology (1995) [Pubmed]
  16. Hepatitis C virus-encoded nonstructural protein NS4A has versatile functions in viral protein processing. Tanji, Y., Hijikata, M., Satoh, S., Kaneko, T., Shimotohno, K. J. Virol. (1995) [Pubmed]
  17. Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. Tomlinson, J.W., Moore, J., Cooper, M.S., Bujalska, I., Shahmanesh, M., Burt, C., Strain, A., Hewison, M., Stewart, P.M. Endocrinology (2001) [Pubmed]
  18. Expression and localization of tissue kallikrein mRNAs in human epidermis and appendages. Komatsu, N., Takata, M., Otsuki, N., Toyama, T., Ohka, R., Takehara, K., Saijoh, K. J. Invest. Dermatol. (2003) [Pubmed]
  19. Rapid detection of the SPINK5 polymorphism Glu420Lys by real-time PCR technology. Rihs, H.P., Kowal, A., Raulf-Heimsoth, M., Degens, P.O., Landt, O., Brüning, T. Clin. Chim. Acta (2005) [Pubmed]
  20. Recurrent focal glomerulosclerosis: natural history and response to therapy. Artero, M., Biava, C., Amend, W., Tomlanovich, S., Vincenti, F. Am. J. Med. (1992) [Pubmed]
  21. Cytologic changes in the nasal secretions during the late nasal response. Pelikan, Z., Pelikan-Filipek, M. J. Allergy Clin. Immunol. (1989) [Pubmed]
  22. A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. Borgoño, C.A., Michael, I.P., Komatsu, N., Jayakumar, A., Kapadia, R., Clayman, G.L., Sotiropoulou, G., Diamandis, E.P. J. Biol. Chem. (2007) [Pubmed]
  23. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Bitoun, E., Micheloni, A., Lamant, L., Bonnart, C., Tartaglia-Polcini, A., Cobbold, C., Al Saati, T., Mariotti, F., Mazereeuw-Hautier, J., Boralevi, F., Hohl, D., Harper, J., Bodemer, C., D'Alessio, M., Hovnanian, A. Hum. Mol. Genet. (2003) [Pubmed]
  24. SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases. Raghunath, M., Tontsidou, L., Oji, V., Aufenvenne, K., Schürmeyer-Horst, F., Jayakumar, A., Ständer, H., Smolle, J., Clayman, G.L., Traupe, H. J. Invest. Dermatol. (2004) [Pubmed]
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