Characterization and function analysis of cathepsin C in Marsupenaeusjaponicus.

Cathepsin C is a cysteine protease widely found in invertebrates and vertebrates, and has the important physiological role participating in proteolysis in vivo and activating various functional proteases in immune/inflammatory cells in the animals. In order to study the role of cathepsin C in the disease resistance of shrimp, we cloned cathepsin C gene (MjcathC) from Marsupenaeus japonicus, analyzed its expression patterns in various tissues, performed MjcathC-knockdown, and finally challenged experimental shrimps with Vibrio alginolyticus and WSSV. The results have shown the full length of MjcathC is 1782 bp, containing an open reading frame of 1350 bp encoding 449 amino acids. Homology analysis revealed that the predicted amino acid sequence of MjcathC shared respectively 88.42 %, 87.36 % and 87.58 % similarity with Penaeus monodon, Fenneropenaeus penicillatus and Litopenaeus vannamei. The expression levels of MjcathC in various tissues of healthy M. japonicus are the highest in the liver, followed by the gills and heart, and the lowest in the stomach. The expression levels of MjcathC were significantly up-regulated in all examined tissues of shrimp challenged with WSSV or V. alginolyticus. After knockdown-MjcathC using RNAi technology in M. japonicus, the expression levels of lectin and heat shock protein 70 in MjcathC-knockdown shrimp were significantly down-regulated, and the mortality of MjcathC-knockdown shrimp challenged by WSSV and V. alginolyticus significantly increased. Knockdown of the MjcathC reduced the resistance of M. japonicus to WSSV and V. alginolyticus. The above results have indicated that cathepsin C may play an important role in the antibacterial and antiviral innate immunity of M. japonicus.

Cathepsin C role in inflammatory gastroenterological, renal, rheumatic, and pulmonary disorders.

Cathepsin C (CatC, syn. Dipeptidyl peptidase I) is a lysosomal cysteine proteinase expressed in several tissues including inflammatory cells. This enzyme is important for maintaining multiple cellular functions and for processing immune cell-derived proteases. While mutations in the CatC gene were reported in Papillon-Lefèvre syndrome, a rare autosomal recessive disorder featuring hyperkeratosis and periodontitis, evidence from clinical and preclinical studies points toward pro-inflammatory effects of CatC in various disease processes that are mainly mediated by the activation of neutrophil serine proteinases. Moreover, tumor-promoting effects were ascribed to CatC. The aim of this review is to highlight current knowledge of the CatC as a potential therapeutic target in inflammatory disorders.

Characterization of a novel dipeptidyl peptidase 1 of Trichinella spiralis and its participation in larval invasion.

The research aimed to describe a new Trichinella spiralis dipeptidyl peptidase 1 (TsDPP1) and investigate its functions in the larval invasion of intestinal epithelial cells (IECs). The gene TsDPP1 was successfully replicated and produced in Escherichia coli BL21 (DE3), showing a strong immune response. TsDPP1 was detected in diverse stages of T. spiralis and showed significant expression in the intestine infective larvae (IIL) and adult worms at 6 days post infection, as confirmed by qPCR and Western blot analysis. The primary localization of TsDPP1 in this parasite was observed in cuticles, stichosomes, and embryos by using the indirect immunofluorescence assay (IIFA). rTsDPP1 exhibited the enzymatic function of natural dipeptidyl peptidase and showed specific binding to IECs, and the binding site was found to be localized on cell membrane. Following transfection with dsRNA-TsDPP1, the expression of TsDPP1 mRNA and protein in muscle larvae (ML) were decreased by approximately 63.52 % and 58.68 %, correspondingly. The activity of TsDPP1 in the ML and IIL treated with dsRNA-TsDPP1 was reduced by 42.98 % and 45.07 %, respectively. The acceleration of larval invasion of IECs was observed with rTsDPP1, while the invasion was suppressed by anti-rTsDPP1 serum. The ability of the larvae treated with dsRNA-TsDPP1 to invade IECs was hindered by 31.23 %. In mice infected with dsRNA-treated ML, the intestinal IIL, and adults experienced a significant decrease in worm burdens and a noticeable reduction in adult female length and fecundity compared to the PBS group. These findings indicated that TsDPP1 significantly impedes the invasion, growth, and reproductive capacity of T. spiralis in intestines, suggesting its potential as a target for anti-Trichinella vaccines.

Papillon-Lefevre syndrome in twelve Egyptian patients: Five novel CTSC variants and functional characterization of a missense variant and its effect on splicing.

OBJECTIVES: describing the clinical features of twelve Egyptian patients with Papillon-Lefever syndrome (PLS). Five novel mutations in the cathepsin C (CTSC) gene are introduced and the phenotype of the syndrome is expanded by the identification of new clinical features. DESIGN: the clinical, oro-dental data of twelve Egyptian patients from seven unrelated families are described. Sequence analysis of the CTSC gene was performed to identify the causative mutaions. RESULTS: Typical PLS features were presented in all patints but with variable severity. One patient showed atypical dental features including dental structural defect, minimal periodontitis, severe gingivitis, and delayed closure of root apices. Another patient presented with arachnodactyly, dystrophic nails, and buphthalmos in the right eye secondary to uncontrolled congenital glaucoma. Mutational analysis of CTSC gene revealed seven distinct homozygous variants including five novel ones: c.285_286delGT (p.Leu96GlufsTer2), c .302 G>C (p.Trp101Ser), c.622_628delCACAGTC (p.H208Efs*11), c.1331delinsAAAAA (p.G444Efs*4) and c .1343 G>A (p.Cys448Tyr). The previously reported missense variant c .757 G>A (p.Ala253Thr) was found in one patient. This variant is very close to the splice region and by functional studies, we proved that it results in exon skipping and early protein truncation (p.R214Sfs*46). CONCLUSION: We report five novel CTSC variants and describe rare and unusual associated clinical and dental findings such as dental structural defects, delayed closure of root apices, and congenital glaucoma. Therefore, our results expand both the phenotypic and mutational spectrum of PLS.

Weighted gene coexpression network analysis reveals negative regulation of hypertrophic cardiomyopathy by carboxylesterase 1 and cathepsin C.

Hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy characterized by hypertrophic cardiomyocytes. It is one of the leading causes of sudden death in adolescents. However, the molecular mechanism of HCM is not clear. In our study, ribonucleic acid (RNA) sequence data of myocardial tissue in HCM patients were extracted from the Gene Expression Omnibus (GEO) database (GSE130036) and analyzed by weighted gene coexpression network analysis (WGCNA). A total of 31 coexpression modules were identified. The coexpression black module significantly correlated with maximum left ventricular wall thickness (Maxi LVWT). We screened the differentially expressed mRNAs between normal tissues and HCM tissues using the dplyr and tidyr packages in R3.6.2. The genes in the black module and differentially expressed genes were further intersected. We found that the expression of carboxylesterase 1 (CES1) and cathepsin C (CTSC) was downregulated in HCM tissues and negatively correlated with Maxi LVWT. We further verified the expression of CES1 and CTSC was downregulated in HCM clinical blood and negatively correlated with Maxi LVWT. Finally, we demonstrated that overexpression of CTSC and CES1 could alleviate HCM in an HCM cell model. In summary, the study suggests that CES1 and CTSC negatively regulate the development of HCM and have potential as therapeutic and diagnostic targets for HCM.

Postoperative chronic pain in arthroplasty papillon-lefèvre syndrome: 17-year dental follow-up: case report / Síndrome de papillon-lefèvre: seguimiento dental de 17 años: reporte de caso

Introduction: The present report describes the case of a 12-year-old patient with 17-year follow-up who was previously diagnosed with Papillon-Lefèvre Syndrome (PLS), which is a rare autosomal recessive irregularity in the cathepsin C gene (CTSC) characterized by palmoplantar hyperkeratosis and premature loss of primary and permanent teeth. Case Report: A specific mutation in the c.203 T > G gene inducing loss of function leading to PLS was detected, as was a mutation in the HLA-DRB1*11 allele, which is associated with this syndrome. There is no consanguinity of the parents, and the siblings are entirely healthy. Early identification of the main characteristics of this syndrome is imperative. Accurate diagnosis by genetic analysis allows differential diagnoses and timely comprehensive dental treatment. Conclusions: Additionally, it allows consultation with a dermatologist to maintain or improve the quality of life of patients with this condition due to progressive worsening and severity of the main physical manifestations. Keywords: Papillon-Lefevre Disease; Keratoderma, Palmo-plantar; Cathepsin C; Periodontitis; Skin Diseases, Genetic; Case reports

Introducción: El presente reporte describe el caso de un paciente de 12 años de edad con 17 años de seguimiento a quien previamente se le diagnosticó Síndrome de Papillon-Lefèvre (PLS), el cual es una rara irregularidad autosómica recesiva en el gen de la catepsina C (CTSC) caracterizada por hiperqueratosis palmoplantar y pérdida prematura de dientes primarios y permanentes. Reporte de Caso: Se detectó una mutación específica en el gen c.203 T > G que induce pérdida de función que conduce a PLS, así como una mutación en el alelo HLA-DRB1*11, que se asocia a este síndrome. No presenta consanguinidad de los padres, padres y hermanos totalmente sanos. La identificación temprana de las principales características de este síndrome es imperativa. El diagnóstico certero por análisis genético permite diagnósticos diferenciales y tratamientos odontológicos integrales oportunos. Conclusiones: Adicionalmente, permite la consulta con un dermatólogo para mantener o mejorar la calidad de vida de los pacientes con esta condición debido al progresivo empeoramiento y severidad de las principales manifestaciones físicas.

Abnormal profiles of cathepsin C secreted in urine of Papillon Lefevre syndrome patients.

BACKGROUND: Papillon Lefevre syndrome (PLS) is an autosomal recessive disorder that results from a mutated gene that encodes a lysosomal peptidase known as cathepsin C (CTSC). The clinical presentation of PLS involves mainly palmoplantar keratosis and periodontitis with a variable degree of severity. SUBJECTS: and methods: Our study included ten patients with a broad spectrum of palmoplantar keratosis and periodontitis severity. CTSC variants were detected by Sanger sequencing. CTSC protein secreted in urine was detected by western blotting. RESULTS: Five patients have missense variants, Four have nonsense variants, and one has splice variants in CTSC. The activation products of cathepsin C protein (Heavy and light chains) were absent in all patients' urine samples except one with a significantly reduced level compared to the controls. The dimeric form of CTSC protein was found in all the studied cases. The monomeric form was found in five cases. The products of proteolytic activation of CTSC by other cathepsins (L and S) were found in the urine samples of five of the patients. Each patient had a characteristic pattern of accumulated CTSC protein maturation/activation substrates, intermediates, and products. 40% of the patients had the activation products of other lysosomal cathepsins. CONCLUSION: Urinary CTSC in PLS patients could be used as a diagnostic biomarker for the biochemical screening of the disease. Different variants in CTSC result in different profiles of CTSC secreted in the urine of PLS patients. The profiles of secreted CTSC in urine could be correlated to the severity of palmoplantar keratosis.

Evolutionary Analysis of Dipeptidyl Peptidase I.

Human dipeptidyl peptidase I (DPPI) belongs to the family of papain-like cysteine peptidases. Its distinctive features are the unique exclusion domain which enables the eponymous activity and homotetramerization of DPPI, and its dependence on chloride ions for enzymatic activity. The oligomeric state of DPPI is unique in this family of predominantly monomeric peptidases. However, a distant DPPI ortholog from Plasmodium falciparum has been shown to be monomeric, indicating that the oligomeric state of DPPI varies between lineages. The aim of this work was to study the evolution of DPPI, with particular attention to the structural features that determine its characteristic enzymatic activity and preferences, and to reconstruct the evolution of its oligomerization. We analyzed fifty-seven selected sequences of DPPI and confirmed its presence in three lineages, namely, Amorphea (including animals and Amoebozoa), Alveolates and the metamonad Giardia. The amino acid residues that bind the chloride ion are highly conserved in all species, indicating that the dependence on chloride ions for activity is an evolutionarily conserved feature of DPPI. The number of N-glycosylation sites is significantly increased in animals, particularly vertebrates. Analysis of homology models and subunit contacts suggests that oligomerization is likely restricted to DPPIs in the Amorphea group.

Downregulation of cathepsin C alleviates endothelial cell dysfunction by suppressing p38 MAPK/NF-κB pathway in preeclampsia.

Endothelial cell dysfunction is an essential pathophysiological feature of preeclampsia (PE). It has been reported that cathepsin C is upregulated in the maternal vascular endothelium of PE patients. The excessive activation of p38 MAPK leads to various diseases, including PE. NF-κB pathway can promote uteroplacental dysfunction, endothelial stress and development of PE. Moreover, it has been verified that cathepsin C can activate p38 MAPK/NF-κB pathway. In the present work, hypoxia/reoxygenation (H/R) injury model of HUVECs was established to discuss the biological functions of cathepsin C in endothelial cell dysfunction and to elucidate the underlying molecular mechanism. The correlation between cathepsin C and p38 MAPK/NF-κB pathway in H/R-stimulated HUVECs as well as the effects of cathepsin C and p38 MAPK/NF-κB pathway on viability, apoptosis, invasion, in vitro angiogenesis of HUVECs and oxidative stress were assessed. The results revealed that H/R injury elevated cathepsin C expression and activated p38 MAPK/NF-κB pathway in HUVECs and cathepsin C knockdown inhibited the activity of p38 MAPK/NF-κB pathway in H/R-stimulated HUVECs. Downregulation of cathepsin C improved viability, inhibited apoptosis and enhanced invasion of H/R-stimulated HUVECs. In addition, downregulation of cathepsin C alleviated oxidative stress and induced stronger HUVEC angiogenesis in vitro. Furthermore, the protective effects of cathepsin C knockdown against endothelial cell dysfunction were reversed by p38 MAPK activator anisomycin. In other words, downregulation of cathepsin C could improve HUVEC viability and enhance anti-apoptotic capacity, anti-oxidative capability, invasive ability, as well as angiogenic potential of H/R-stimulated HUVECs by repressing p38 MAPK/NF-κB pathway.

Exome Sequencing of 5 Families with Severe Early-Onset Periodontitis.

Periodontitis is characterized by alveolar bone loss leading to tooth loss. A small proportion of patients develop severe periodontitis at the juvenile or adolescent age without exposure to the main risk factors of the disease. It is considered that these cases carry rare variants with large causal effects, but the specific variants are largely unknown. In this study, we performed exome sequencing of 5 families with children who developed stage IV, grade C, periodontitis between 3 and 18 y of age. In 1 family, we found compound heterozygous variants in the gene CTSC (p.R272H, p.G139R), 1 of which was previously identified in a family with prepubertal periodontitis. Subsequent targeted resequencing of the CTSC gene in 24 patients <25 y of age (stage IV, grade C) identified the known mutation p.I453V (odds ratio = 4.06, 95% CI = 1.6 to 10.3, P = 0.001), which was previously reported to increase the risk for adolescent periodontitis. An affected sibling of another family carried a homozygous deleterious mutation in the gene TUT7 (p.R560Q, CADD score >30 [Combined Annotation Dependent Depletion]), which is implicated in regulation of interleukin 6 expression. Two other affected siblings shared heterozygous deleterious mutations in the interacting genes PADI1 and FLG (both CADD = 36), which contribute to the integrity of the environment-tissue barrier interface. Additionally, we found predicted deleterious mutations in the periodontitis risk genes ABCA1, GLT6D1, and SIGLEC5. We conclude that the CTSC variants p.R272H and p.I453V have different expressivity and diagnostic relevance for prepubertal and adolescent periodontitis, respectively. We propose additional causal variants for early-onset periodontitis, which also locate within genes that carry known susceptibility variants for common forms. However, the genetic architecture of juvenile periodontitis is complex and differs among the affected siblings of the sequenced families.

A rare CTSC mutation in Papillon-Lefèvre Syndrome results in abolished serine protease activity and reduced NET formation but otherwise normal neutrophil function.

Papillon-Lefèvre Syndrome (PLS) is an autosomal recessive monogenic disease caused by loss-of-function mutations in the CTSC gene, thus preventing the synthesis of the protease Cathepsin C (CTSC) in a proteolytically active form. CTSC is responsible for the activation of the pro-forms of the neutrophil serine proteases (NSPs; Elastase, Proteinase 3 and Cathepsin G), suggesting its involvement in a variety of neutrophil functions. In PLS neutrophils, the lack of CTSC protease activity leads to inactivity of the NSPs. Clinically, PLS is characterized by an early, typically pre-pubertal, onset of severe periodontal pathology and palmoplantar hyperkeratosis. However, PLS is not considered an immune deficiency as patients do not typically suffer from recurrent and severe (bacterial and fungal) infections. In this study we investigated an unusual CTSC mutation in two siblings with PLS, a 503A>G substitution in exon 4 of the CTSC gene, expected to result in an amino acid replacement from tyrosine to cysteine at position 168 of the CTSC protein. Both patients bearing this mutation presented with pronounced periodontal pathology. The characteristics and functions of neutrophils from patients homozygous for the 503A>G CTSC mutation were compared to another previously described PLS mutation (755A>T), and a small cohort of healthy volunteers. Neutrophil lysates from patients with the 503A>G substitution lacked CTSC protein and did not display any CTSC or NSP activity, yet neutrophil counts, morphology, priming, chemotaxis, radical production, and regulation of apoptosis were without any overt signs of alteration. However, NET formation upon PMA-stimulation was found to be severely depressed, but not abolished, in PLS neutrophils.

Cathepsin C Regulates Cytokine-Induced Apoptosis in ß-Cell Model Systems.

Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated destruction of the pancreatic ß cells. We previously reported that the T1D candidate gene cathepsin H is downregulated by pro-inflammatory cytokines in human pancreatic islets and regulates ß-cell function, apoptosis, and disease progression in children with new-onset T1D. In the present study, the objective was to investigate the expression patterns of all 15 known cathepsins in ß-cell model systems and examine their role in the regulation of cytokine-induced apoptosis. Real-time qPCR screening of the cathepsins in human islets, 1.1B4 and INS-1E ß-cell models identified several cathepsins that were expressed and regulated by pro-inflammatory cytokines. Using small interfering RNAs to knock down (KD) the cytokine-regulated cathepsins, we identified an anti-apoptotic function of cathepsin C as KD increased cytokine-induced apoptosis. KD of cathepsin C correlated with increased phosphorylation of JNK and p38 mitogen-activated protein kinases, and elevated chemokine CXCL10/IP-10 expression. This study suggests that cathepsin C is a modulator of ß-cell survival, and that immune modulation of cathepsin expression in islets may contribute to immune-mediated ß-cell destruction in T1D.

Cathepsin C inhibitors as anti-inflammatory drug discovery: Challenges and opportunities.

Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.

Cathepsin C aggravates neuroinflammation via promoting production of CCL2 and CXCL2 in glial cells and neurons in a cryogenic brain lesion.

OBJECTIVE: Chemokines regulate infiltration of immune cells to brain in inflammation. Cathepsin C (CatC), a lysosomal protease, has been found to participate in neuroinflammation. However, how CatC affects chemokines expression in neuroinflammation triggered by traumatic brain injury (TBI) remains unclear. Here, we investigated the effects of CatC on chemokines and neuroinflammation in TBI. METHODS: The present study used CatC knockdown (KD) and overexpression (OE) mice to generate cryogenic brain lesion model and determined effects of CatC on expression of chemokines CCL2, CCL5 and CXCL2 and infiltration of immune cells in acute and chronic phases of the lesion. Further, cellular sources of various chemokines were demonstrated in vitro. Values were compared with wild type (WT) mice. RESULTS: The results found that 6 h after lesion, CatC expression,IL-1ß and TNF-α mRNA and protein expression were strongly induced in the lesions; CCL2 and CXCL2 mRNA and protein expression were increased in CatC OE mice, while decreased in CatC KD mice. On the 3rd day after lesion, macrophages and neutrophils were mainly infiltrated to the lesions. Simultaneously, Iba-1+ cells in CatC OE mice were increased, while MPO + cells in CatC KD mice were decreased. In contrast, on the 28th day after lesion, a few lymphocytes were infiltrated surrounding new blood vessels. CatC OE mice showed larger volumes of scar areas, higher expression of CCL2,CXCL2,IL-1ß,TNF-α,IL-6 and iNOS, as well as stronger GFAP+ and Iba-1+ signals, while CatC KD mice had reversed effects. No significant differences of CCL5 expression were found in various genotype mice. Further, in vitro study demonstrated CatC-induced expression of CCL2 were mainly derived from microglia and neurons, while CXCL2 derived from microglia and astrocytes. CONCLUSION: Our data indicate that CatC aggravates neuroinflammation via promoting production of CCL2 and CXCL2 in glial cells and neurons in a cryogenic brain lesion, providing potential cellular and molecular targets for future intervention of TBI and other neuroinflammatory diseases.

A novel missense variant in cathepsin C gene leads to PLS in a Chinese patient: A case report and literature review.

BACKGROUND: Papilon-Lefevre syndrome (PLS; OMIM 245000) is a rare autosomal recessive disease characterized by aggressive periodontitis and palmoplantar keratoderma. The prevalence of PLS in the general population is one to four cases per million. Although the etiology and pathogenic mechanisms underlying PLS remain largely unclear, existing evidence shows loss-of-function mutations of the cathepsin C gene (CTSC; OMIM 602365) could cause PLS. Here we found a novel variant of the CTSC gene in a Chinese PLS family and predicted the effect of the variant on the physic-chemical characters and tertiary structure of the protein. METHODS: The 1-7 coding exons and exon-intron boundaries of CTSC gene of the proband and her family were amplified and sequenced directly, and Chromas was used to read sequencing files. Furthermore, the PolyPhen-2, PROVEAN, and Mutation Taster were utilized to predict the pathogenicity of the variant. Besides, the physic-chemical and structural characters of the protein were analyzed by ProtParam, ProtScale, and SWISS-MODEL. RESULTS: Our study identified a novel homozygous variant c.763T>C (p.Cys255Arg) in exon 6 of the CTSC gene, and it was a likely pathogenic variant as predicted by PolyPhen-2, PROVEAN, and Mutation Taster. Moreover, ProtParam and Protscale revealed the variant increased the isoelectric point and hydrophilicity of the protein, and the SWISS-MODEL analysis suggested the variant was located in a critical domain for protein activity. CONCLUSION: Our study analyzed a Chinese family with PLS and identified a novel missense variant in the CTSC gene. Besides, this study retrospectively summarized 113 variants of CTSC in the world and highlighted the features of 27 CTSC variants in Chinese PLS patients. In addition, this study paid much particular attention to the relationship between CTSC variants and different phenotypes.

Two patients with Papillon-Lefèvre syndrome without periodontal involvement of the permanent dentition.

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive genodermatosis characterized by palmoplantar keratoderma and severe periodontitis leading to premature loss of primary and permanent teeth. PLS is caused by loss-of-function mutations in CTSC, lacking functional cathepsin C, which impairs the activation of neutrophil serine proteases. Precise pathogenesis of periodontal damage is unknown. Patient 1 presented with well-demarcated, transgredient, diffuse, palmoplantar keratoderma and psoriasiform lesions from the age of 2 years. Based on severe and recurrent periodontal inflammation, his dentist had diagnosed PLS at the age of 3 years and provided a strict oral hygiene regimen with repeated adjunct antibiotic therapies. Oral acitretin 10 mg/day along with tretinoin ointment at the age of 9 greatly improved palmoplantar keratoderma. Aged 18 years, the patient exhibited an intact permanent dentition and absence of periodontal disease. Patient 2, a 30-year-old man, suffered from transgredient, diffuse, palmoplantar keratoderma with fissuring from the age of 2 months, marked psoriasiform plaques on elbows and knees, and nail dystrophy. Intriguingly, without specific dental treatment, teeth and dental records were unremarkable. He was referred with a suspected diagnosis of psoriasis. Both patients were otherwise healthy, blood tests and sonography of internal organs were within normal limits. Panel sequencing revealed loss-of-function mutations in CTSC, c.322A>T (p.Lys108Ter) and c.504C>G (p.Tyr168Ter) in patient 1 and homozygous c.415G>T (p.Gly139Ter) in patient 2. The final diagnosis of unusual PLS was made. PLS should be considered in palmoplantar keratoderma lacking periodontitis or tooth loss.

A novel mutation in the cathepsin C (CTSC) gene in Iranian family with Papillon-Lefevre syndrome.

OBJECTIVES: In this study, we analyzed the whole exomes of CTSC gene in a family with history of PLS. MATERIALS AND METHODS: Genomic DNA was extracted from peripheral blood and genotype analysis was performed. The mutated protein sequence was used to find the best possible tertiary structure for homology modeling. The homology modeling of the novel mutation was then performed using the online Swiss-Prot server. The results were also analyzed for to verify its validity. RESULTS: The analysis of CTSC gene elucidated a novel insertion GAC. The novel mutation was proved by analyzing 50 healthy control volunteers. Modeling of the novel found mutation in CTSC gene revealed structural defects that may have caused the functional abnormalities. CONCLUSIONS: The structural analysis of the mutated protein model identifies changes in the stereo-chemical and the energy level of the mutated protein. Since this protein play a role in the activation of granule serine proteases from cytotoxic T lymphocytes, natural killer cells, mast cells, such structural defects may lead to its malfunction causing dysfunctioning of immune defense mechanisms.

The CTSC-RAB38 Fusion Transcript Is Associated With the Risk of Hemorrhage in Brain Arteriovenous Malformations.

Brain arteriovenous malformations (bAVMs) are congenital anomalies of blood vessels that cause intracranial hemorrhage in children and young adults. Chromosomal rearrangements and fusion genes play an important role in tumor pathogenesis, though the role of fusion genes in bAVM pathophysiological processes is unclear. The aim of this study was to identify fusion transcripts in bAVMs and analyze their effects. To identify fusion transcripts associated with bAVM, RNA sequencing was performed on 73 samples, including 66 bAVM and 7 normal cerebrovascular samples, followed by STAR-Fusion analysis. Reverse transcription polymerase chain reaction and Sanger sequencing were applied to verify fusion transcripts. Functional pathway analysis was performed to identify potential effects of different fusion types. A total of 21 fusion transcripts were detected. Cathepsin C (CTSC)-Ras-Related Protein Rab-38 (RAB38) was the most common fusion and was detected in 10 of 66 (15%) bAVM samples. In CTSC-RAB38 fusion-positive samples, CTSC and RAB38 expression was significantly increased and activated immune/inflammatory signaling. Clinically, CTSC-RAB38 fusion bAVM cases had a higher hemorrhage rate than non-CTSC-RAB38 bAVM cases (p < 0.05). Our study identified recurrent CTSC-RAB38 fusion transcripts in bAVMs, which may be associated with bAVM hemorrhage by promoting immune/inflammatory signaling.