RESUMO
Papillon-Lefèvre syndrome (PLS) is an autosomal recessive rare disease, main characteristics of which include palmoplantar hyperkeratosis and premature edentulism due to advanced periodontitis (formerly aggressive periodontitis). This study aimed to characterize the oral phenotype, including salivary parameters, and the salivary microbiome of three PLS sisters, comparatively. Two sisters were toothless (PLSTL1 and PLSTL2), and one sister had most of the teeth in the oral cavity (PLST). Total DNA was extracted from the unstimulated saliva, and the amplicon sequencing of the 16S rRNA gene fragment was performed in an Ion PGM platform. The amplicon sequence variants (ASVs) were obtained using the DADA2 pipeline, and the taxonomy was assigned using the SILVA v.138. The main phenotypic characteristics of PLS were bone loss and premature loss of primary and permanent dentition. The PLST sister presented advanced periodontitis with gingival bleeding and suppuration, corresponding to the advanced periodontitis as a manifestation of systemic disease, stage IV, grade C. All three PLS sisters presented hyposalivation as a possible secondary outcome of the syndrome. Interestingly, PLST salivary microbiota was dominated by the uncultured bacteria Bacterioidales (F0058), Fusobacterium, Treponema, and Sulfophobococcus (Archaea domain). Streptococcus, Haemophilus, and Caldivirga (Archaea) dominated the microbiome of the PLSTL1 sister, while the PLSTL2 had higher abundances of Lactobacillus and Porphyromonas. This study was the first to show a high abundance of organisms belonging to the Archaea domain comprising a core microbiome in human saliva. In conclusion, a PLST individual does have a microbiota different from that of the periodontitis' aggressiveness previously recognized. Due to an ineffective cathepsin C, the impairment of neutrophils probably provided a favorable environment for the PLS microbiome. The interactions of Bacteroidales F0058, Caldivirga, and Sulfophobococcus with the microbial consortium of PLS deserves future investigation. Traditional periodontal therapy is not efficient in PLS patients. Unraveling the PLS microbiome is essential in searching for appropriate treatment and avoiding early tooth loss.
Assuntos
Periodontite Agressiva , Microbiota , Doença de Papillon-Lefevre , Periodontite Agressiva/genética , Periodontite Agressiva/microbiologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Doença de Papillon-Lefevre/genética , Doença de Papillon-Lefevre/microbiologia , Fenótipo , RNA Ribossômico 16S/genética , Saliva/microbiologiaRESUMO
Papillon-Lefèvre syndrome (PLS; MIM#245000) is a rare recessive autosomal disorder characterized by palmar and plantar hyperkeratosis, and aggressively progressing periodontitis leading to premature loss of deciduous and permanent teeth. PLS is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. PLS clinical expressivity is highly variable and no consistent genotype-phenotype correlation has been demonstrated yet. Here we report the clinical and genetic features of five PLS patients presenting a severe periodontal breakdown in primary and permanent dentition, hyperkeratosis over palms and soles, and recurrent sinusitis and/or tonsillitis. Mutation analysis revealed two novel homozygous recessive mutations (c.947T>C and c.1010G>C) and one previous described homozygous recessive mutation (c.901G>A), with parents carrying them in heterozygous, in three families (four patients). The fourth family presented with the CTSC c.628C>T mutation in heterozygous, which was inherited maternally. Patient carrying the CTSC c.628C>T mutation featured classical PLS phenotype, but no PLS clinical characteristics were found in his carrier mother. All mutations were found to affect directly (c.901G>A, c.947T>C, and c.1010G>C) or indirectly (c.628C>T, which induces a premature termination) the heavy chain of the cathepsin C, the region responsible for activation of the lysosomal protease. Together, these findings indicate that both homozygous and heterozygous mutations in the cathepsin C heavy chain domain may lead to classical PLS phenotype, suggesting roles for epistasis or gene-environment interactions on determination of PLS phenotypes.
Assuntos
Doença de Papillon-Lefevre/genética , Doença de Papillon-Lefevre/patologia , Adolescente , Adulto , Catepsina C/química , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Modelos Moleculares , Doença de Papillon-Lefevre/diagnóstico por imagem , Adulto JovemRESUMO
BACKGROUND: Papillon-Lefèvre Syndrome (PLS) is a type IV genodermatosis caused by mutations in cathepsin C (CTSC), with a worldwide prevalence of 1-4 cases per million in the general population. In México, the prevalence of this syndrome is unknown, and there are few case reports. The diagnosis of twenty patients in the state of Sinaloa highlights the need to characterize this syndrome in Mexicans. METHODS: To understand the basis of PLS in Mexicans, the gene expression, enzymatic activity and mutational analysis of CTSC were assayed in nine PLS patients and their relatives. Frequencies of CTSC gene polymorphisms and HLA alleles were determined in these patients, their relatives, and the population. RESULTS: Patients showed normal CTSC gene expression, but a deep reduction (up to 85%) in enzymatic activity in comparison to unrelated healthy individuals. A novel loss-of-function mutation, c.203 T > G (p.Leu68Arg), was found in all patients, and some carried the polymorphism c.458C > T (p.Thr153Ile). Allelic frequencies in patients, relatives and controls were 88.89%, 38.24% and 0.25% for G (c.203 T > G); and 11.11%, 8.82% and 9.00% for T (c.458C > T). HLA-DRB1*11 was found significantly more frequent (P = 0.0071) in patients than controls (33.33% vs. 7.32%), with an estimated relative risk of 6.33. CONCLUSIONS: The novel loss-of function mutation of CTSC gene (c.203 T > G) found in patients correlated with their diminished enzymatic activity, and HLA-DRB1*11 was found to be associated with PLS. The study of more PLS patients may give more insights into the etiology of the disease as well as its prevalence in México.
Assuntos
Catepsina C/genética , Mutação , Doença de Papillon-Lefevre/genética , Adolescente , Adulto , Catepsina C/metabolismo , Criança , Pré-Escolar , Feminino , Expressão Gênica , Frequência do Gene , Cadeias HLA-DRB1/genética , Humanos , Lactente , Masculino , México , Pessoa de Meia-Idade , Polimorfismo Conformacional de Fita Simples , Adulto JovemRESUMO
PURPOSE: Papilion-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder that involves palmoplantar keratosis (PK) and severe aggressive periodontitis. Cathepsin C (CTSC) gene mutations are etiologic for PLS, with more than 60 different mutations reported in different ethnic groups worldwide. The purpose of this study was to report a novel cathepsin C mutation in a Brazilian patient. METHODS: A 4-year-old boy presented with aggressive periodontitis, recession, missing teeth, and hyperkeratosis of the palms of hands and soles. Peripheral blood samples were obtained from family members for genomic DNA isolation. The coding region and exon/intron boundaries of the CTSC gene were amplified and sequenced. RESULTS: The patient had a PLS phenotype, which included PK and early-onset severe periodontitis. Sequence analysis showed a novel CTSC mutation (c.267-268del) present in the homozygous state. CONCLUSION: This report described a novel mutation in a family with Brazilian Papillon-Lefèvre syndrome and presented a review of all cathepsin C (65) mutations reported to date.
Assuntos
Catepsina C/genética , Doença de Papillon-Lefevre/genética , Brasil , Pré-Escolar , Consanguinidade , Humanos , Masculino , Mutação , Doença de Papillon-Lefevre/enzimologia , Linhagem , FenótipoRESUMO
Haim-Munk syndrome (HMS) is a rare autosomal recessive disorder characterized clinically by abnormal palmoplantar hyperkeratosis and destruction of the periodontium, with hallmarks of onychogryphosis and arachnodactyly. Germline mutations in the lysosomal protease cathepsin C gene (CTSC) have been described in a single patient with HMS and in several individuals with the clinically related disorder Papillon-Lefevre syndrome (PLS). We describe a patient with HMS. We have analysed the cathepsin C gene in the proband and her mother. Sequence analysis of CTSC in the proband revealed a homozygous mutation at codon 196 (587T-->C) within exon 4 that altered the conserved leucine to proline (Leu196Pro), whereas the patient's mother was heterozygous for that mutation. The same mutation has previously been described in an unrelated Brazilian family with PLS. An identical single missense mutation in the cathepsin C gene may underlie both PLS and HMS. These findings confirm that HMS and PLS are allelic variants of cathepsin C gene mutations and suggest that other factors (environmental or genetic) may be important determinants of the clinical phenotype of HMS and PLS.
Assuntos
Catepsina C/genética , Ceratodermia Palmar e Plantar/genética , Mutação , Adulto , Feminino , Homozigoto , Humanos , Ceratodermia Palmar e Plantar/patologia , Doença de Papillon-Lefevre/genética , Linhagem , Análise de Sequência de DNA , SíndromeRESUMO
Papillon-Lefèvre syndrome (PLS) is an autosomal recessive palmoplantar keratoderma caused by cathepsin C (CTSC) gene mutations. This study reports CTSC mutational and enzyme analyses in a consanguineous Brazilian family with PLS, representing the first enzymatic analysis of a Brazilian kinship with PLS. This family segregates a novel PLS-related mutation, p.W185X, that is associated with a complete loss of enzymatic activity.
Assuntos
Catepsina C/genética , Doença de Papillon-Lefevre/genética , Mutação Puntual , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sequência de Bases , Brasil , Consanguinidade , Sequência Conservada , DNA/genética , Análise Mutacional de DNA , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos , Especificidade da EspécieRESUMO
BACKGROUND: Papillon-Lefèvre syndrome (PLS) is a disorder that involves destruction of the periodontium and abnormal hyperkeratosis of the palms of the hands and soles of the feet. Mutations of the lysosomal protease cathepsin C gene (CTSC) have been associated with PLS. However, genotypic and phenotypic correlation has not been established. In the present study we investigated the CTSC gene in a Brazilian cohort affected by PLS. METHODS: Eight consanguineous members of a kindred with PLS were studied. DNA was extracted and all exons of the gene amplified by the polymerase chain reaction (PCR) using specific primers. Mutations were identified by DNA sequencing of the coding region and introns of the CTSC gene. RESULTS: Sequence analysis of CTSC from subjects affected by PLS identified a novel mutation (587T --> C) in exon 4, predicted to cause a Leu196Pro amino acid substitution. Three of 3 subjects were homozygous for cathepsin C mutations inherited from a common ancestor. One patient was heterozygous and showed plantar hyperkeratosis without periodontal disease. Two other family members were also heterozygous but did not present palmoplantar hyperkeratosis and/or periodontal disease. CONCLUSIONS: This study describes a novel mutation of the cathepsin C gene in a Brazilian kindred with Papillon-Lefèvre syndrome.
Assuntos
Periodontite Agressiva/genética , Catepsina C/genética , Doença de Papillon-Lefevre/genética , Adolescente , Periodontite Agressiva/etiologia , Substituição de Aminoácidos , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Leucina/genética , Masculino , Mutação de Sentido Incorreto , Doença de Papillon-Lefevre/complicações , Doença de Papillon-Lefevre/enzimologia , Linhagem , Reação em Cadeia da Polimerase , Prolina/genéticaRESUMO
Foram estudados três irmäos, portadores de ceratose palmoplantar transgressiva associada à periodontopatia, com perda dos elementos dentários temporários e permanentes, com marcada consaguinidade entre os pais, avós e bisavós, mostrando tratar-se de herança autossômica recessiva, preenchendo os critérios da síndrome de Papillon-Lefèvre, condiçäo rara que merece contínua investigaçäo.
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Periodontite Agressiva/etiologia , Consanguinidade , Doença de Papillon-Lefevre/genética , Ceratodermia Palmar e Plantar/etiologia , Evolução Clínica , Síndrome de Marfan , Manifestações Bucais , Retinoides , Manifestações CutâneasRESUMO
Dentro del grupo de la queratodermias palmo-plantares, con padrón hereditario autosómico recesivo, se describe el síndrome de Papillon-lefevre, asociado entre otras anomalias con alteraciones dentales y calcificaciones intracraneales. Reportamos el caso de dos familias afectadas con el sindrome, hacemos una breve revisón de la literatura, estudio genético-clínico de las familias, y se recalca la importancia del consejo genético, como forma de prevención.