HGNC Approved Gene Symbol:SPINK5
Cytogenetic location:5q32 Genomic coordinates(GRCh38) :5:148,063,980-148,137,382 (from NCBI)
The SPINK5 gene, which resides on 5q31-q32, encodes a 15-domain serine protease inhibitor, LEKTI, that is expressed in epithelial and mucosal surfaces and in the thymus.
Magert et al. (1999) described the serine protease inhibitor LEKTI ('lymphoepithelial Kazal-type-related inhibitor') in thymus and mucous epithelia as the precursor to proteolytic fragments, one of which was found to exert an antitrypsin activity in vitro. The entire precursor protein, as deduced from the nucleotide sequence of the cloned cDNA, includes 15 potential inhibitory domains, 13 of which exhibit a Kazal-type-derived 4-cysteine-residue pattern that represents a novel protein module of serine protease inhibitor. Northern blot analysis and RT-PCR detected expression of LEKTI in thymus, vaginal epithelium, Bartholin gland, oral mucosa, tonsil, and parathyroid gland.
Galliano et al. (2005) showed that the mouse Spink5 gene is transcribed into 2 mRNAs with different 3-prime UTRs. Both mRNAs encode the same protein, which shares 60% identity with human SPINK5. Mouse Spink5 has a 70-amino acid deletion, covering the entire Kazal-type domain 6 and the linker region between domains 6 and 7, compared with human SPINK5. In situ hybridization and immunohistochemical analysis of various mouse tissues detected Spink5 expression restricted to the granular layer of epidermis, the suprabasal layers of stratified epithelia, thymic Hassall bodies, and differentiated epithelia of the thymus medulla, a pattern similar to that of human SPINK5. Western blot analysis of endogenous Spink5 and deglycosylated Spink5 showed a drop from 130 kD to 120 kD, indicating protein glycosylation.
By a combination of database mining and PCR,Chavanas et al. (2000) elucidated the intron-exon layout of the SPINK5 gene. The SPINK5 gene comprises 33 exons and spans approximately 61 kb.
Yang et al. (2004) determined that the mouse Spink5 gene contains 32 exons. The exon-intron junctions are well conserved between the mouse and human genes.
By PCR-based radiation hybrid mapping,Magert et al. (1999) localized the SPINK5 gene to chromosome 5q31-q32.
Yang et al. (2004) mapped the mouse Spink5 gene to a region of chromosome 18B3 that shows homology of synteny to human chromosome 5q32.
LEKTI was the first serine-protease inhibitor shown to be primarily involved in a skin disorder or hair morphogenesis, namely, Netherton syndrome (NETH;256500). Together with the identification of mutations in cathepsin C (602365) in Papillon-Lefevre syndrome (245000), the study ofChavanas et al. (2000) underscored the importance of the regulation of proteolysis in epithelia formation and keratinocyte terminal differentiation. Whereas other disorders of keratinization feature hyperkeratosis, a diminution or loss of the granular and horny layers is described in Netherton syndrome patients, suggesting that SPINK5 mutations cause a distinctive defect in skin barrier function in Netherton syndrome. Defective cornification may favor recurrent infections and inflammation, but the observed tissue specificity of LEKTI also suggests a specific role in the thymus (Magert et al., 1999). Abnormal maturation of T lymphocytes in Netherton syndrome patients may disrupt the regulation of T-helper-2-cell (Th2) responsiveness to allergens, which drives the acute hypersensitivity response and IgE (147180) levels.Chavanas et al. (2000) noted that genetic variants of the pro-Th2 interleukins 4 (147780) and 13 (147683), the IL4 receptor alpha subunit (147781), and the IL13 receptor alpha-1 subunit (300119) had been shown to be associated with atopy, asthma, and IgE levels. Mutations in the recombination-inactivating genes RAG1 (179615) and RAG2 (179616) underlie Omenn syndrome (603554), a severe immunodeficiency with erythroderma and a skewed Th2 lymphocyte profile. The findings ofChavanas et al. (2000) indicated the existence of a novel pathway distinct from interleukin signaling and V(D)J recombination accounting for the regulation of T2 lymphocytes.
Using in situ hybridization,Komatsu et al. (2002) showed that SPINK5 transcripts are expressed in the uppermost stratum spinosum and stratum granulosum of the epidermis. Strong hybridization signals were also observed in hair follicle epithelium and sebaceous glands. In stratum corneum samples from Netherton syndrome patients from 2 families with different SPINK5 mutations and different cutaneous phenotypes, the hydrolytic (trypsin-like; see276000) activity was markedly increased compared with that in normal controls, clearly indicating that serine proteases in the stratum corneum are overactive in Netherton syndrome patients. Furthermore, the degree of increase in trypsin-like activity was correlated with the severity of skin lesions and the sites of truncation of the SPINK5 proprotein.Komatsu et al. (2002) hypothesized that defective inhibitory regulation of SPINK5-derived peptides due to the gene mutations in netherton syndrome patients result in increased protease activity in the stratum corneum, accelerated degradation of desmoglein-1 (125670), and overdesquamation of corneocytes. Colocalization of SPINK5 transcripts with SCTE (605643)/SCCE (604438) proteins in hair follicles suggested that the regulation of these proteases' activity by the SPINK5-derived inhibitors may also affect hair growth and morphogenesis.Komatsu et al. (2002) suggested that Netherton syndrome may not be an ichthyosis characterized by the retention of thick adherent scales but a disease of overdesquamation causing severe skin permeability barrier dysfunction.
Using immunocytochemistry,Bitoun et al. (2003) showed that LEKTI was strongly expressed in the granular and uppermost spinous layers of the epidermis, and in differentiated layers of stratified epithelia. Western blot analysis identified a 145-kD full-length protein and a shorter 125-kD isoform in normal differentiated human primary keratinocytes (HK). Both proteins were N-glycosylated and rapidly processed in a post-endoplasmic reticulum compartment into at least 3 C-terminal fragments. Processing was prevented in HK by treatment with a furin inhibitor. In contrast, LEKTI precursors and proteolytic fragments were not detected in differentiated HK from Netherton syndrome patients. Defective expression of LEKTI in skin sections was a constant feature in Netherton syndrome patients, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature of Netherton syndrome.
Netherton Syndrome
Netherton syndrome is a severe autosomal recessive disorder characterized by congenital ichthyosis with defective cornification, a specific hair shaft defect ('bamboo hair'), and severe atopic manifestations.Chavanas et al. (2000) localized the gene defective in Netherton syndrome to 5q32 by linkage analysis and homozygosity mapping. As proteolysis is critical in cell activation and communication, and because some serine protease inhibitors had been shown to downregulate the proinflammatory NFKB (see164011) pathway,Chavanas et al. (2000) considered the SPINK5 gene, which maps to that locus, a plausible candidate for Netherton syndrome. Mutation analysis identified 11 different mutations in 13 families (see, e.g.,605010.0001-605010.0003), at least 9 of which generated premature termination codons and predicted mRNA instability. The mutations included a nonsense mutation, 4 mononucleotide insertions, 2 mono/dinucleotide deletions, and 4 splice site mutations. Consistent with the recessive mode of inheritance of Netherton syndrome, these results predicted null expression of the mutated SPINK5 alleles through accelerated mRNA decay or loss of function of truncated LEKTI polypeptides if any were translated in the patients.
Sprecher et al. (2001) ascertained 19 unrelated Comel-Netherton syndrome families of various ethnic backgrounds. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 families. The nucleotide changes included 4 nonsense mutations, 8 small deletions or insertions leading to frameshift, and 5 splice site defects, all of which were expected to result in premature termination or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including 2 recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKTI are associated with a severe phenotype.Sprecher et al. (2001) reported for the first time the use of molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comel-Netherton syndrome.
Bitoun et al. (2002) characterized SPINK5 mutations in Netherton syndrome patients from 21 families of different geographic origin and identified 18 mutations, of which 13 were novel and 7 (39%) were recurrent. The majority of the mutations were clustered between exons 1 through 8 and exons 21 through 26. They comprised 4 nonsense mutations (22%), 8 frameshift insertions or deletions (44%), and 6 splice site defects (33%). All mutations predicted the formation of premature termination codons. Northern blot analysis showed variable reduction of SPINK5 mutant transcript levels, suggesting variable efficiency of nonsense-mediated mRNA decay. Seven patients were homozygotes, 8 were compound heterozygotes, and 5 were heterozygotes. Five mutations, 1 of which resulted in perinatal lethal disease in 3 families, were associated with certain ethnic groups.Bitoun et al. (2002) also described 45 intragenic polymorphisms in the patients studied. The clinical features of erythroderma, trichorrhexis invaginata, and atopic manifestations were present in the majority of affected individuals, and ichthyosis linearis circumflexa was seen in 12 of 24 patients. No clear correlation between mutation and phenotype was seen, suggesting that the degree of severity may be influenced by other factors.
In 9 unrelated children from diverse ethnic backgrounds with Netherton syndrome,Renner et al. (2009) sequenced the SPINK5 gene and identified biallelic mutations in 8 patients (see, e.g.,605010.0005 and605010.0006); in 1 patient, only 1 mutation was detected, and in another patient, no mutations were found. However, in all 9 patients, LEKTI protein expression was absent or present as small immunoreactive foci in fewer than 2% of epithelial cells from skin biopsies and/or buccal mucosa.
In an 8-month-old Polish boy with Netherton syndrome,Smigiel et al. (2017) identified compound heterozygosity for mutations in the SPINK5 gene (605010.0005 and605010.0007).
In a Muslim Arab girl with Netherton syndrome and intestinal atresia, who died of sepsis at 11 months of age,Nevet et al. (2017) identified homozygosity for a 1-bp deletion in the SPINK5 gene (605010.0008).
SPINK5 Polymorphisms
Walley et al. (2001) identified 6 coding polymorphisms in the SPINK5 gene and found that a glu420-to-lys variant (E420K;605010.0004) showed significant association with atopy (see147050), atopic dermatitis (605845), and asthma (see600807) in 2 independent panels of families. The results implicated a previously unrecognized pathway for the development of common allergic illnesses.
Kato et al. (2003) analyzed 8 polymorphisms in exons 13 and 14 of the SPINK5 gene in 124 Japanese patients with atopic dermatitis and 110 controls, and found significant associations (p less than 0.03) between 7 of the polymorphisms, including E420K (605010.0004), and atopic dermatitis. They found no significant difference between serum IgE levels and SPINK5 genotype.
Yang et al. (2004) inactivated the Spink5 gene in mice. Heterozygous mutant mice were phenotypically normal. Skin development in homozygous embryos was not significantly altered at embryonic day 15.5, but by day 17.5, the stratum corneum began to peel off and there was focal detachment of granular cells. At birth, detachment of the stratum corneum was widespread. Loss of cell-cell adhesion and a complete loss of barrier function resulted in perinatal death due to dehydration. Mutant stratum corneum showed increased proteolytic activity, with premature degradation of extracellular desmosomal components.
Hewett et al. (2005) created mice with an R820X mutation in the Spink5 gene. Newborn homozygotes developed a severe ichthyosis with a loss of skin barrier function and dehydration, resulting in death within a few hours. Biochemical analysis of skin revealed a substantial increase in the proteolytic processing of profilaggrin (135940) into its constituent filaggrin monomers.Hewett et al. (2005) suggested that in the absence of SPINK5 there is an abnormal increase in the processing of profilaggrin, and that this may play a direct role in the observed deficit in the adhesion of the stratum corneum and the severely compromised epidermal barrier function.
Descargues et al. (2005) found that Spink5 -/- mice faithfully replicated key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation, and a skin barrier defect. Deficiency of the serine protease inhibitor LEKTI caused abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein-1 (DSG1;125670) due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme-like hyperactivity. This led to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin (135940) processing was increased and implicated LEKTI in the cornification process. The findings ofDescargues et al. (2005) identified LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein-1 as the primary pathogenic event in Netherton syndrome.
In a Spink5 -/- mouse model,Sales et al. (2010) demonstrated that the membrane protease matriptase (606797) initiated Netherton syndrome by premature activation of a pro-kallikrein (see147910) cascade. Autoactivation of proinflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from Spink5 -/- mice dampened inflammation, eliminated aberrant protease activity, prevented detachment of the stratum corneum, and improved the barrier function of the epidermis.
In a patient with Netherton syndrome (NETH;256500),Chavanas et al. (2000) found a homozygous C-to-T transition in exon 25 of the SPINK5 gene that converted codon 790 from CGA (arg) to TGA (stop).
In affected members of a family with Netherton syndrome (NETH;256500),Chavanas et al. (2000) found compound heterozygosity for an A-to-T transversion at the 3-prime end of intron 4 of the SPINK5 gene, converting the canonical AG to TG. The mutation on the other allele was a single nucleotide insertion in exon 26 (2468insA;605010.0003). Whereas the first mutation altered splicing, the insertion caused frameshift with a premature termination codon for the residues downstream of the mutation.
In affected members of 3 Kashmir families with Netherton syndrome (NETH;256500),Chavanas et al. (2000) found a homozygous single nucleotide insertion in exon 26 of the SPINK5 gene, converting a run of 10 adenines to a run of 11, with resulting frameshift and premature termination codon 4 residues downstream of the insertion. Only 2 of these 3 Kashmir families were known to be related. This mutation was also find in compound heterozygosity with an intron 4 splice site mutation (605010.0002) in a fourth, unrelated family.
This variant, formerly titled SUSCEPTIBILITY TO ATOPY, SUSCEPTIBILITY TO ATOPIC DERMATITIS 6, and SUSCEPTIBILITY TO ASTHMA, has been reclassified as a polymorphism based on its frequency in the ExAC database (Hamosh, 2017).
In exon 14 of the SPINK5 gene,Walley et al. (2001) found a single-nucleotide polymorphism (SNP), a 1258G-A transition, that caused a missense change, glu420-to-lys. They found significant associations of maternally derived alleles between atopy (147050), atopic dermatitis (605845), asthma (600807), and the total serum IgE and lys420. Paternally derived alleles tended to be less often associated with disease than maternal alleles. SPINK5 is at the distal end of a cytokine cluster that extends from D5S490 (134 cM from the 'top' of the chromosome) to CSF1R (164770) at position 153 cM.Walley et al. (2001) emphasized that it was not clear from their study whether the SPINK5 polymorphism was primarily associated with atopic dermatitis, asthma, or the general atopic state.
Kato et al. (2003) analyzed the E420K polymorphism in 124 Japanese patients with atopic dermatitis and 110 controls and found that the GG genotype (E/E) was significantly less frequent (p = 0.023) in the atopic dermatitis group.
Hamosh (2017) noted that the 1258G-A variant was found in 61,019 of 120,144 alleles and in 16,138 homozygotes in the ExAC database, with an allele frequency of 0.5079 (July 31, 2017).
In a 6-month-old girl (patient 1) with Netherton syndrome (NETH;256500),Renner et al. (2009) identified compound heterozygosity for a splicing mutation (c.1431-12G-A) in intron 15 of the SPINK5 gene, and a 4-bp deletion (c.354_357delTTGT;605010.0006). In a 9-year-old boy (patient 4) with Netherton syndrome, they identified the splice site mutation in heterozygosity, but did not detect another mutation in SPINK5. However, in both patients, LEKTI protein expression was absent or present only as small immunoreactive foci in fewer than 2% of epithelial cells. Segregation of the mutations with disease was not reported. Both patients had recurrent/persistent infections of the skin and gastrointestinal and respiratory tracts, associated with sepsis and hypernatremic dehydration.
In an 8-month-old Polish boy with Netherton syndrome, who had recurrent episodes of hypernatremic dehydration,Smigiel et al. (2017) identified compound heterozygosity for the SPINK5 c.1431-12G-A (c.1431-12G-A, NM_001127698.1) splicing mutation and another splicing mutation, c.1816_1820+21delinsCT (605010.0007). The c.1816_1820+21delinsCT mutation was inherited from his mother, who reported a history of alopecia from early childhood; however, her skin was observed to be smooth and without keratinizing changes. DNA was unavailable from the father.
For discussion of the 4-bp deletion (c.354_357delTTGT) in the SPINK5 gene, that was found in compound heterozygous state in a 6-month-old girl with Netherton syndrome (NETH;256500) byRenner et al. (2009), see605010.0005.
For discussion of the deletion/insertion (c.1816_1820+21delinsCT, NM_001127698.1) in intron 19 of the SPINK5 gene, that was found in compound heterozygous state in an 8-month-old Polish boy with Netherton syndrome (NETH;256500) bySmigiel et al. (2017), see605010.0005.
In a Muslim Arab girl with Netherton syndrome and intestinal atresia (NETH;256500), who died of sepsis at 11 months of age,Nevet et al. (2017) identified homozygosity for a 1-bp deletion (c.995delT) in exon 11 of the SPINK5 gene, causing a frameshift predicted to result in a premature termination codon (Met332SerfsTer43). Her unaffected parents were heterozygous for the mutation.
Bitoun, E., Chavanas, S., Irvine, A. D., Lonie, L., Bodemer, C., Paradisi, M., Hamel-Teillac, D., Ansai, S., Mitsuhashi, Y., Taieb, A., de Prost, Y., Zambruno, G., Harper, J. I., Hovnanian, A.Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J. Invest. Derm. 118: 352-361, 2002. [PubMed:11841556,related citations] [Full Text]
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.LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Hum. Molec. Genet. 12: 2417-2430, 2003. [PubMed:12915442,related citations] [Full Text]
Chavanas, S., Bodemer, C., Rochat, A., Hamel-Teillac, D., Ali, M., Irvine, A. D., Bonafe, J.-L., Wilkinson, J., Taieb, A., Barrandon, Y., Harper, J. I., de Prost, Y., Hovnanian, A.Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nature Genet. 25: 141-142, 2000. [PubMed:10835624,related citations] [Full Text]
Chavanas, S., Garner, C., Bodemer, C., Ali, M., Hamel-Teillac, D., Wilkinson, J., Bonafe, J.-L., Paradisi, M., Kelsell, D. P., Ansai S., Mitsuhashi, Y., Larregue, M., Leigh, I. M., Harper, J. I., Taieb, A., de Prost, Y., Cardon, L. R., Hovnanian, A.Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping. Am. J. Hum. Genet. 66: 914-921, 2000. [PubMed:10712206,images,related citations] [Full Text]
Descargues, P., Deraison, C., Bonnart, C., Kreft, M., Kishibe, M., Ishida-Yamamoto, A., Elias, P., Barrandon, Y., Zambruno, G., Sonnenberg, A., Hovnanian, A.Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nature Genet. 37: 56-65, 2005. [PubMed:15619623,related citations] [Full Text]
Galliano, M. F., Roccasecca, R. M., Descargues, P., Micheloni, A., Levy, E., Zambruno, G., D'Alessio, M., Hovnanian, A.Characterization and expression analysis of the Spink5 gene, the mouse ortholog of the defective gene in Netherton syndrome. Genomics 85: 483-492, 2005. [PubMed:15780751,related citations] [Full Text]
Hamosh, A.Personal Communication. Baltimore, Md. July 31, 2017.
Hewett, D. R., Simons, A. L., Mangan, N. E., Jolin, H. E., Green, S. M., Fallon, P. G., McKenzie, A. N. J.Lethal, neonatal ichthyosis with increased proteolytic processing of filaggrin in a mouse model of Netherton syndrome. Hum. Molec. Genet. 14: 335-346, 2005. [PubMed:15590704,related citations] [Full Text]
Kato, A., Fukai, K., Oiso, N., Hosomi, N., Murakami, T., Ishii, M.Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Brit. J. Derm. 148: 665-669, 2003. [PubMed:12752122,related citations] [Full Text]
Komatsu, N., Takata, M., Otsuki, N., Ohka, R., Amano, O., Takehara, K., Saijoh, K.Stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides. J. Invest. Derm. 118: 436-443, 2002. [PubMed:11874482,related citations] [Full Text]
Magert, H.-J., Standker, L., Kreutzmann, P., Zucht, H.-D., Reinecke, M., Sommerhoff, C. P., Fritz, H., Forssmann, W.-G.LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J. Biol. Chem. 274: 21499-21502, 1999. [PubMed:10419450,related citations] [Full Text]
Nevet, M. J., Indelman, M., Ben-Ari, J., Bergman, R.A case of Netherton syndrome with intestinal atresia, a novel SPINK5 mutation, and a fatal course. Int. J. Derm. 56: 1055-1057, 2017. [PubMed:28832989,related citations] [Full Text]
Renner, E. D., Hartl, D., Rylaarsdam, S., Young, M. L., Monaco-Shawver, L., Kleiner, G., Markert, L., Stiehm, E. R., Belohradsky, B. H., Upton, M. P., Torgerson, T. R., Orange, J. S., Ochs, H. D.Comel-Netherton syndrome defined as primary immunodeficiency. J. Allergy Clin. Immun. 124: 536-543, 2009. Note: Erratum: J. Allergy Clin. Immun. 124: 1318 only, 2009. [PubMed:19683336,images,related citations] [Full Text]
Sales, K. U., Masedunskas, A., Bey, A. L., Rasmussen, A. L., Weigert, R., List, K., Szabo, R., Overbeek, P. A., Bugge, T. H.Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nature Genet. 42: 676-683, 2010. [PubMed:20657595,images,related citations] [Full Text]
Smigiel, R., Krolak-Olejnik, B., Sniegorska, D., Roznsztrauch, A., Szafranska, A., Sasiadek, M. M., Wertheim-Tysarowska, K.Is c.1431-12G-A a common European mutation of SPINK5? Report of a patient with Netherton syndrome. Balkan J. Med. Genet. 19: 81-84, 2017. [PubMed:28289593,images,related citations] [Full Text]
Sprecher, E., Chavanas, S., DiGiovanna, J. J., Amin, S., Nielsen, K., Prendiville, J. S., Silverman, R., Esterly, N. B., Spraker, M. K., Guelig, E., Larralde de Luna, M., Williams, M. L., Buehler, B., Siegfried, E. C., Van Maldergem, L., Pfendner, E., Bale, S. J., Uitto, J., Hovnanian, A., Richard, G.The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. J. Invest. Derm. 117: 179-187, 2001. [PubMed:11511292,related citations] [Full Text]
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. C. M.Gene polymorphism in Netherton and common atopic disease. Nature Genet. 29: 175-178, 2001. [PubMed:11544479,related citations] [Full Text]
Yang, T., Liang, D., Koch, P. J., Hohl, D., Kheradmand, F., Overbeek, P. A.Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5(-/-) mice. Genes Dev. 18: 2354-2358, 2004. [PubMed:15466487,images,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: SPINK5
SNOMEDCT: 312514006, 34638006;
Cytogenetic location: 5q32 Genomic coordinates(GRCh38) : 5:148,063,980-148,137,382(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 5q32 | Netherton syndrome | 256500 | Autosomal recessive | 3 |
The SPINK5 gene, which resides on 5q31-q32, encodes a 15-domain serine protease inhibitor, LEKTI, that is expressed in epithelial and mucosal surfaces and in the thymus.
Magert et al. (1999) described the serine protease inhibitor LEKTI ('lymphoepithelial Kazal-type-related inhibitor') in thymus and mucous epithelia as the precursor to proteolytic fragments, one of which was found to exert an antitrypsin activity in vitro. The entire precursor protein, as deduced from the nucleotide sequence of the cloned cDNA, includes 15 potential inhibitory domains, 13 of which exhibit a Kazal-type-derived 4-cysteine-residue pattern that represents a novel protein module of serine protease inhibitor. Northern blot analysis and RT-PCR detected expression of LEKTI in thymus, vaginal epithelium, Bartholin gland, oral mucosa, tonsil, and parathyroid gland.
Galliano et al. (2005) showed that the mouse Spink5 gene is transcribed into 2 mRNAs with different 3-prime UTRs. Both mRNAs encode the same protein, which shares 60% identity with human SPINK5. Mouse Spink5 has a 70-amino acid deletion, covering the entire Kazal-type domain 6 and the linker region between domains 6 and 7, compared with human SPINK5. In situ hybridization and immunohistochemical analysis of various mouse tissues detected Spink5 expression restricted to the granular layer of epidermis, the suprabasal layers of stratified epithelia, thymic Hassall bodies, and differentiated epithelia of the thymus medulla, a pattern similar to that of human SPINK5. Western blot analysis of endogenous Spink5 and deglycosylated Spink5 showed a drop from 130 kD to 120 kD, indicating protein glycosylation.
By a combination of database mining and PCR, Chavanas et al. (2000) elucidated the intron-exon layout of the SPINK5 gene. The SPINK5 gene comprises 33 exons and spans approximately 61 kb.
Yang et al. (2004) determined that the mouse Spink5 gene contains 32 exons. The exon-intron junctions are well conserved between the mouse and human genes.
By PCR-based radiation hybrid mapping, Magert et al. (1999) localized the SPINK5 gene to chromosome 5q31-q32.
Yang et al. (2004) mapped the mouse Spink5 gene to a region of chromosome 18B3 that shows homology of synteny to human chromosome 5q32.
LEKTI was the first serine-protease inhibitor shown to be primarily involved in a skin disorder or hair morphogenesis, namely, Netherton syndrome (NETH; 256500). Together with the identification of mutations in cathepsin C (602365) in Papillon-Lefevre syndrome (245000), the study of Chavanas et al. (2000) underscored the importance of the regulation of proteolysis in epithelia formation and keratinocyte terminal differentiation. Whereas other disorders of keratinization feature hyperkeratosis, a diminution or loss of the granular and horny layers is described in Netherton syndrome patients, suggesting that SPINK5 mutations cause a distinctive defect in skin barrier function in Netherton syndrome. Defective cornification may favor recurrent infections and inflammation, but the observed tissue specificity of LEKTI also suggests a specific role in the thymus (Magert et al., 1999). Abnormal maturation of T lymphocytes in Netherton syndrome patients may disrupt the regulation of T-helper-2-cell (Th2) responsiveness to allergens, which drives the acute hypersensitivity response and IgE (147180) levels. Chavanas et al. (2000) noted that genetic variants of the pro-Th2 interleukins 4 (147780) and 13 (147683), the IL4 receptor alpha subunit (147781), and the IL13 receptor alpha-1 subunit (300119) had been shown to be associated with atopy, asthma, and IgE levels. Mutations in the recombination-inactivating genes RAG1 (179615) and RAG2 (179616) underlie Omenn syndrome (603554), a severe immunodeficiency with erythroderma and a skewed Th2 lymphocyte profile. The findings of Chavanas et al. (2000) indicated the existence of a novel pathway distinct from interleukin signaling and V(D)J recombination accounting for the regulation of T2 lymphocytes.
Using in situ hybridization, Komatsu et al. (2002) showed that SPINK5 transcripts are expressed in the uppermost stratum spinosum and stratum granulosum of the epidermis. Strong hybridization signals were also observed in hair follicle epithelium and sebaceous glands. In stratum corneum samples from Netherton syndrome patients from 2 families with different SPINK5 mutations and different cutaneous phenotypes, the hydrolytic (trypsin-like; see 276000) activity was markedly increased compared with that in normal controls, clearly indicating that serine proteases in the stratum corneum are overactive in Netherton syndrome patients. Furthermore, the degree of increase in trypsin-like activity was correlated with the severity of skin lesions and the sites of truncation of the SPINK5 proprotein. Komatsu et al. (2002) hypothesized that defective inhibitory regulation of SPINK5-derived peptides due to the gene mutations in netherton syndrome patients result in increased protease activity in the stratum corneum, accelerated degradation of desmoglein-1 (125670), and overdesquamation of corneocytes. Colocalization of SPINK5 transcripts with SCTE (605643)/SCCE (604438) proteins in hair follicles suggested that the regulation of these proteases' activity by the SPINK5-derived inhibitors may also affect hair growth and morphogenesis. Komatsu et al. (2002) suggested that Netherton syndrome may not be an ichthyosis characterized by the retention of thick adherent scales but a disease of overdesquamation causing severe skin permeability barrier dysfunction.
Using immunocytochemistry, Bitoun et al. (2003) showed that LEKTI was strongly expressed in the granular and uppermost spinous layers of the epidermis, and in differentiated layers of stratified epithelia. Western blot analysis identified a 145-kD full-length protein and a shorter 125-kD isoform in normal differentiated human primary keratinocytes (HK). Both proteins were N-glycosylated and rapidly processed in a post-endoplasmic reticulum compartment into at least 3 C-terminal fragments. Processing was prevented in HK by treatment with a furin inhibitor. In contrast, LEKTI precursors and proteolytic fragments were not detected in differentiated HK from Netherton syndrome patients. Defective expression of LEKTI in skin sections was a constant feature in Netherton syndrome patients, demonstrating that loss of LEKTI expression in the epidermis is a diagnostic feature of Netherton syndrome.
Netherton Syndrome
Netherton syndrome is a severe autosomal recessive disorder characterized by congenital ichthyosis with defective cornification, a specific hair shaft defect ('bamboo hair'), and severe atopic manifestations. Chavanas et al. (2000) localized the gene defective in Netherton syndrome to 5q32 by linkage analysis and homozygosity mapping. As proteolysis is critical in cell activation and communication, and because some serine protease inhibitors had been shown to downregulate the proinflammatory NFKB (see 164011) pathway, Chavanas et al. (2000) considered the SPINK5 gene, which maps to that locus, a plausible candidate for Netherton syndrome. Mutation analysis identified 11 different mutations in 13 families (see, e.g., 605010.0001-605010.0003), at least 9 of which generated premature termination codons and predicted mRNA instability. The mutations included a nonsense mutation, 4 mononucleotide insertions, 2 mono/dinucleotide deletions, and 4 splice site mutations. Consistent with the recessive mode of inheritance of Netherton syndrome, these results predicted null expression of the mutated SPINK5 alleles through accelerated mRNA decay or loss of function of truncated LEKTI polypeptides if any were translated in the patients.
Sprecher et al. (2001) ascertained 19 unrelated Comel-Netherton syndrome families of various ethnic backgrounds. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 families. The nucleotide changes included 4 nonsense mutations, 8 small deletions or insertions leading to frameshift, and 5 splice site defects, all of which were expected to result in premature termination or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including 2 recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKTI are associated with a severe phenotype. Sprecher et al. (2001) reported for the first time the use of molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comel-Netherton syndrome.
Bitoun et al. (2002) characterized SPINK5 mutations in Netherton syndrome patients from 21 families of different geographic origin and identified 18 mutations, of which 13 were novel and 7 (39%) were recurrent. The majority of the mutations were clustered between exons 1 through 8 and exons 21 through 26. They comprised 4 nonsense mutations (22%), 8 frameshift insertions or deletions (44%), and 6 splice site defects (33%). All mutations predicted the formation of premature termination codons. Northern blot analysis showed variable reduction of SPINK5 mutant transcript levels, suggesting variable efficiency of nonsense-mediated mRNA decay. Seven patients were homozygotes, 8 were compound heterozygotes, and 5 were heterozygotes. Five mutations, 1 of which resulted in perinatal lethal disease in 3 families, were associated with certain ethnic groups. Bitoun et al. (2002) also described 45 intragenic polymorphisms in the patients studied. The clinical features of erythroderma, trichorrhexis invaginata, and atopic manifestations were present in the majority of affected individuals, and ichthyosis linearis circumflexa was seen in 12 of 24 patients. No clear correlation between mutation and phenotype was seen, suggesting that the degree of severity may be influenced by other factors.
In 9 unrelated children from diverse ethnic backgrounds with Netherton syndrome, Renner et al. (2009) sequenced the SPINK5 gene and identified biallelic mutations in 8 patients (see, e.g., 605010.0005 and 605010.0006); in 1 patient, only 1 mutation was detected, and in another patient, no mutations were found. However, in all 9 patients, LEKTI protein expression was absent or present as small immunoreactive foci in fewer than 2% of epithelial cells from skin biopsies and/or buccal mucosa.
In an 8-month-old Polish boy with Netherton syndrome, Smigiel et al. (2017) identified compound heterozygosity for mutations in the SPINK5 gene (605010.0005 and 605010.0007).
In a Muslim Arab girl with Netherton syndrome and intestinal atresia, who died of sepsis at 11 months of age, Nevet et al. (2017) identified homozygosity for a 1-bp deletion in the SPINK5 gene (605010.0008).
SPINK5 Polymorphisms
Walley et al. (2001) identified 6 coding polymorphisms in the SPINK5 gene and found that a glu420-to-lys variant (E420K; 605010.0004) showed significant association with atopy (see 147050), atopic dermatitis (605845), and asthma (see 600807) in 2 independent panels of families. The results implicated a previously unrecognized pathway for the development of common allergic illnesses.
Kato et al. (2003) analyzed 8 polymorphisms in exons 13 and 14 of the SPINK5 gene in 124 Japanese patients with atopic dermatitis and 110 controls, and found significant associations (p less than 0.03) between 7 of the polymorphisms, including E420K (605010.0004), and atopic dermatitis. They found no significant difference between serum IgE levels and SPINK5 genotype.
Yang et al. (2004) inactivated the Spink5 gene in mice. Heterozygous mutant mice were phenotypically normal. Skin development in homozygous embryos was not significantly altered at embryonic day 15.5, but by day 17.5, the stratum corneum began to peel off and there was focal detachment of granular cells. At birth, detachment of the stratum corneum was widespread. Loss of cell-cell adhesion and a complete loss of barrier function resulted in perinatal death due to dehydration. Mutant stratum corneum showed increased proteolytic activity, with premature degradation of extracellular desmosomal components.
Hewett et al. (2005) created mice with an R820X mutation in the Spink5 gene. Newborn homozygotes developed a severe ichthyosis with a loss of skin barrier function and dehydration, resulting in death within a few hours. Biochemical analysis of skin revealed a substantial increase in the proteolytic processing of profilaggrin (135940) into its constituent filaggrin monomers. Hewett et al. (2005) suggested that in the absence of SPINK5 there is an abnormal increase in the processing of profilaggrin, and that this may play a direct role in the observed deficit in the adhesion of the stratum corneum and the severely compromised epidermal barrier function.
Descargues et al. (2005) found that Spink5 -/- mice faithfully replicated key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation, and a skin barrier defect. Deficiency of the serine protease inhibitor LEKTI caused abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein-1 (DSG1; 125670) due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme-like hyperactivity. This led to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin (135940) processing was increased and implicated LEKTI in the cornification process. The findings of Descargues et al. (2005) identified LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein-1 as the primary pathogenic event in Netherton syndrome.
In a Spink5 -/- mouse model, Sales et al. (2010) demonstrated that the membrane protease matriptase (606797) initiated Netherton syndrome by premature activation of a pro-kallikrein (see 147910) cascade. Autoactivation of proinflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from Spink5 -/- mice dampened inflammation, eliminated aberrant protease activity, prevented detachment of the stratum corneum, and improved the barrier function of the epidermis.
In a patient with Netherton syndrome (NETH; 256500), Chavanas et al. (2000) found a homozygous C-to-T transition in exon 25 of the SPINK5 gene that converted codon 790 from CGA (arg) to TGA (stop).
In affected members of a family with Netherton syndrome (NETH; 256500), Chavanas et al. (2000) found compound heterozygosity for an A-to-T transversion at the 3-prime end of intron 4 of the SPINK5 gene, converting the canonical AG to TG. The mutation on the other allele was a single nucleotide insertion in exon 26 (2468insA; 605010.0003). Whereas the first mutation altered splicing, the insertion caused frameshift with a premature termination codon for the residues downstream of the mutation.
In affected members of 3 Kashmir families with Netherton syndrome (NETH; 256500), Chavanas et al. (2000) found a homozygous single nucleotide insertion in exon 26 of the SPINK5 gene, converting a run of 10 adenines to a run of 11, with resulting frameshift and premature termination codon 4 residues downstream of the insertion. Only 2 of these 3 Kashmir families were known to be related. This mutation was also find in compound heterozygosity with an intron 4 splice site mutation (605010.0002) in a fourth, unrelated family.
This variant, formerly titled SUSCEPTIBILITY TO ATOPY, SUSCEPTIBILITY TO ATOPIC DERMATITIS 6, and SUSCEPTIBILITY TO ASTHMA, has been reclassified as a polymorphism based on its frequency in the ExAC database (Hamosh, 2017).
In exon 14 of the SPINK5 gene, Walley et al. (2001) found a single-nucleotide polymorphism (SNP), a 1258G-A transition, that caused a missense change, glu420-to-lys. They found significant associations of maternally derived alleles between atopy (147050), atopic dermatitis (605845), asthma (600807), and the total serum IgE and lys420. Paternally derived alleles tended to be less often associated with disease than maternal alleles. SPINK5 is at the distal end of a cytokine cluster that extends from D5S490 (134 cM from the 'top' of the chromosome) to CSF1R (164770) at position 153 cM. Walley et al. (2001) emphasized that it was not clear from their study whether the SPINK5 polymorphism was primarily associated with atopic dermatitis, asthma, or the general atopic state.
Kato et al. (2003) analyzed the E420K polymorphism in 124 Japanese patients with atopic dermatitis and 110 controls and found that the GG genotype (E/E) was significantly less frequent (p = 0.023) in the atopic dermatitis group.
Hamosh (2017) noted that the 1258G-A variant was found in 61,019 of 120,144 alleles and in 16,138 homozygotes in the ExAC database, with an allele frequency of 0.5079 (July 31, 2017).
In a 6-month-old girl (patient 1) with Netherton syndrome (NETH; 256500), Renner et al. (2009) identified compound heterozygosity for a splicing mutation (c.1431-12G-A) in intron 15 of the SPINK5 gene, and a 4-bp deletion (c.354_357delTTGT; 605010.0006). In a 9-year-old boy (patient 4) with Netherton syndrome, they identified the splice site mutation in heterozygosity, but did not detect another mutation in SPINK5. However, in both patients, LEKTI protein expression was absent or present only as small immunoreactive foci in fewer than 2% of epithelial cells. Segregation of the mutations with disease was not reported. Both patients had recurrent/persistent infections of the skin and gastrointestinal and respiratory tracts, associated with sepsis and hypernatremic dehydration.
In an 8-month-old Polish boy with Netherton syndrome, who had recurrent episodes of hypernatremic dehydration, Smigiel et al. (2017) identified compound heterozygosity for the SPINK5 c.1431-12G-A (c.1431-12G-A, NM_001127698.1) splicing mutation and another splicing mutation, c.1816_1820+21delinsCT (605010.0007). The c.1816_1820+21delinsCT mutation was inherited from his mother, who reported a history of alopecia from early childhood; however, her skin was observed to be smooth and without keratinizing changes. DNA was unavailable from the father.
For discussion of the 4-bp deletion (c.354_357delTTGT) in the SPINK5 gene, that was found in compound heterozygous state in a 6-month-old girl with Netherton syndrome (NETH; 256500) by Renner et al. (2009), see 605010.0005.
For discussion of the deletion/insertion (c.1816_1820+21delinsCT, NM_001127698.1) in intron 19 of the SPINK5 gene, that was found in compound heterozygous state in an 8-month-old Polish boy with Netherton syndrome (NETH; 256500) by Smigiel et al. (2017), see 605010.0005.
In a Muslim Arab girl with Netherton syndrome and intestinal atresia (NETH; 256500), who died of sepsis at 11 months of age, Nevet et al. (2017) identified homozygosity for a 1-bp deletion (c.995delT) in exon 11 of the SPINK5 gene, causing a frameshift predicted to result in a premature termination codon (Met332SerfsTer43). Her unaffected parents were heterozygous for the mutation.
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