Functional <i>Cathepsin C</i> mutations cause different Papillon–Lefèvre syndrome phenotypes

Noack, Barbara; Görgens, Heike; Schacher, Beate; Puklo, Magda; Eickholz, Peter; Hoffmann, Thomas; Schackert, Hans K.

doi:10.1111/j.1600-051x.2008.01201.x

Cited by 33 publications

(43 citation statements)

References 40 publications

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“…In addition, the zymogens of NE, CG, and PR3 are also lost by degradation, continuous secretion, or other unknown mechanisms (23). To study the consequences of a complete cathepsin C deficiency on the fate of NSP4, we analyzed PLS neutrophils from a patient with a homozygous Pro 285 Leu mutation (14). Fig.…”

Section: Patients With Pls Lack Nsp4 In Their Neutrophilsmentioning

confidence: 99%

“…T nucleotide exchange in the cathepsin C gene, leading to a substitution of the normal proline residue 285 by leucine (Pro 285 Leu mutation). This mutation has already been reported and characterized and was associated with an almost complete loss of protein function (14). PMN were isolated from heparinized peripheral blood and either activated or fully lysed as described above.…”

Section: Biotinylation Of Absmentioning

confidence: 99%

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NSP4 Is Stored in Azurophil Granules and Released by Activated Neutrophils as Active Endoprotease with Restricted Specificity

Perera

Wiesmüller

Larsen

et al. 2013

The Journal of Immunology

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Whereas neutrophil elastase, cathepsin G, and proteinase 3 have been known as granule-associated serine proteases of neutrophils for decades, a fourth member, called neutrophil serine protease 4 (NSP4), was just recently described and provisionally characterized. In this study, we identified NSP4 as a novel azurophil granule protein of neutrophils by Western blot analyses of subcellular fractions as well as by RT-PCR analyses of neutrophil precursors from human bone marrow. The highest mRNA levels were observed in myeloblasts and promyelocytes, similar to myeloperoxidase, a marker of azurophil granules. To determine the extended sequence specificity of recombinant NSP4, we used an iterative fluorescence resonance energy transfer-based optimization strategy. In total, 142 different peptide substrates with arginine in P1 and variations at the P1', P2', P3, P4, and P2 positions were tested. This enabled us to construct an alpha(1)-proteinase inhibitor variant (Ile-Lys-Pro-Arg-/-Ser-Ile-Pro) with high specificity for NSP4. This tailor-made serpin was shown to form covalent complexes with all NSP4 of neutrophil lysates and supernatants of activated neutrophils, indicating that NSP4 is fully processed and stored as an already activated enzyme in azurophil granules. Moreover, cathepsin C was identified as the activator of NSP4 in vivo, as cathepsin C deficiency resulted in a complete absence of NSP4 in a Papillon-Lefevre patient. Our in-depth analysis of NSP4 establishes this arginine-specific protease as a genuine member of preactivated serine proteases stored in azurophil granules of human neutrophils

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Section: Patients With Pls Lack Nsp4 In Their Neutrophilsmentioning

confidence: 99%

Section: Biotinylation Of Absmentioning

confidence: 99%

NSP4 Is Stored in Azurophil Granules and Released by Activated Neutrophils as Active Endoprotease with Restricted Specificity

Perera

Wiesmüller

Larsen

et al. 2013

The Journal of Immunology

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“…Papillon-Lefèvre Syndrome (PLS) is a rare autosomal recessive disease caused by mutations in the gene encoding lysosomal cysteine protease cathepsin C (CTSC) (1)(2)(3), also known as dipeptidyl peptidase I (DPPI) (4). CTSC is expressed mainly in hematopoietic tissues.…”

Section: Introductionmentioning

confidence: 99%

Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses

Sørensen¹,

Clemmensen²,

Dahl³

et al. 2014

J. Clin. Invest.

144

173

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Papillon-Lefèvre syndrome (PLS) results from mutations that inactivate cysteine protease cathepsin C (CTSC), which processes a variety of serine proteases considered essential for antimicrobial defense. Despite serine protease-deficient immune cell populations, PLS patients do not exhibit marked immunodeficiency. Here, we characterized a 24-year-old woman who had suffered from severe juvenile periodontal disease, but was otherwise healthy, and identified a homozygous missense mutation in CTSC indicative of PLS. Proteome analysis of patient neutrophil granules revealed that several proteins that normally localize to azurophil granules, including the major serine proteases, elastase, cathepsin G, and proteinase 3, were absent. Accordingly, neutrophils from this patient were incapable of producing neutrophil extracellular traps (NETs) in response to ROS and were unable to process endogenous cathelicidin hCAP-18 into the antibacterial peptide LL-37 in response to ionomycin. In immature myeloid cells from patient bone marrow, biosynthesis of CTSC and neutrophil serine proteases appeared normal along with initial processing and sorting to cellular storage. In contrast, these proteins were completely absent in mature neutrophils, indicating that CTSC mutation promotes protease degradation in more mature hematopoietic subsets, but does not affect protease production in progenitor cells. Together, these data indicate CTSC protects serine proteases from degradation in mature immune cells and suggest that neutrophil serine proteases are dispensable for human immunoprotection.

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“…Kobayashi et al, however, explained the late presentation of PLS periodontitis with atypical clinical feature of retention of all the permanent teeth at over 40 years of age by identifying a novel CTSC homozygous nonsense mutation, p.Lys106X, which leads to a deficiency of the mutant mRNA because of nonsense-mediated mRNA decay [64]. Therefore, the phenotypic variability of the PLS associated with identical genetic background may reflect the influence of additional genetic and/or environmental factors on disease characteristics [65].…”

Section: Atypical Plsmentioning

confidence: 99%

Syndromes That Include Both Palmoplantar Keratoderma And Severe Periodontitis: A Review

Dababneh¹

2013

Dentistry

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Palmoplantar keratodermas (PPK) include a heterogeneous group of disorders with overlapping clinical features. The main aspect of PPK is thickening and hyperkeratosis of the palmar and plantar skin, that may be hereditary or acquired; diffuse, focal, or punctuate; and transgrediens or progrediens. PPKs are further distinguished by their mode of inheritance and by the presence of certain associated clinical features. Periodontitis was reported in association with more than one syndrome characterized by PPK. An extensively reported one is the Papillon-Lefévre syndrome (PLS) which is characterized by early onset of PPK and periodontitis affecting the primary and secondary dentitions. In addition to PLS, Haim-Munk, HOPP, Variant Carvajal and Weary-Kindler are other syndromes manifested by PPK and reported in association with severe periodontitis. Atypical cases of PLS were also reported, such as partial expression or a late presentation of the syndrome. The aim of this article is to critically review the literature concerned with Papillon-Lefévre syndrome in its typical and atypical clinical presentation, in addition to other syndromes manifested at the same time by PPK and severe periodontitis.Thorough history and medical examination, together with periodontal, dermatologic, and genetic counseling, are important to exclude other existing medical conditions or other syndromes that might need special attention and care.

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Functional Cathepsin C mutations cause different Papillon–Lefèvre syndrome phenotypes

Cited by 33 publications

References 40 publications

NSP4 Is Stored in Azurophil Granules and Released by Activated Neutrophils as Active Endoprotease with Restricted Specificity

NSP4 Is Stored in Azurophil Granules and Released by Activated Neutrophils as Active Endoprotease with Restricted Specificity

Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defenses

Syndromes That Include Both Palmoplantar Keratoderma And Severe Periodontitis: A Review

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