RESUMO
BACKGROUND: Rare highly penetrant gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) can lead to psoriasis, a chronic inflammatory disease of the skin and other organs. OBJECTIVES: To investigate the contribution of rare CARD14 variants to psoriasis in the Tunisian population and to expand knowledge of CARD14 variants in the European population. METHODS: CARD14 coding exons were resequenced in patients with psoriasis and controls from Tunisia and Europe, including 16 European cases with generalized pustular psoriasis (GPP). Novel variants were evaluated for their effect on nuclear factor (NF)-κB signalling. RESULTS: Rare variants in CARD14 were significantly enriched in Tunisian cases compared with controls. Three were collectively found in 5% of Tunisian cases, and all affected the N-terminal region of the protein harbouring its caspase recruitment domain or coiled-coil domain. These variants were c.349G>A (p.Gly117Ser), c.205C>T (p.Arg69Trp) and c.589G>A (p.Glu197Lys). c.589G>A (p.Glu197Lys) led to upregulation of NF-κB activity in a similar manner to that of previously described psoriasis-associated mutations. p.Arg69Trp led to sevenfold downregulation of NF-κB activity. One Tunisian case harboured a c.1356+5G>A splice alteration that is predicted to lead to loss of exon 9, which encodes part of the coiled-coil domain. No cases of GPP harboured an interleukin-36RN mutation, but one of 16 cases of GPP with a family history of psoriasis vulgaris harboured a c.1805C>T (p.Ser602Leu) mutation in CARD14. CONCLUSIONS: These observations provide further insights into the genetic basis of psoriasis in the Tunisian population and provide functional information on novel CARD14 variants seen in cases from Tunisia and other populations.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Guanilato Ciclase/genética , Proteínas de Membrana/genética , Mutação/genética , Psoríase/genética , População Branca/genética , Adulto , Regulação para Baixo/genética , Feminino , Humanos , Masculino , NF-kappa B/metabolismo , Psoríase/etnologia , Transdução de Sinais , Tunísia , Regulação para Cima/genética , População Branca/etnologia , Adulto JovemRESUMO
BACKGROUND: Recently, it has been shown that a deletion in the late cornified envelope (LCE) gene cluster (LCE3C_LCE3B-del) is associated with susceptibility to psoriasis in European and Asian populations. However, no study of this deletion has been performed in the North African population. The aim of the present study was to investigate whether this deletion is associated with familial psoriasis in Tunisian population. METHODS: A total of 34 patients and 55 healthy individuals were recruited from 7 multiplex families and a PCR assay was used to determine the association of this deletion. Its effect on susceptibility to psoriasis was assessed using the PDT program. RESULTS: We failed to detect any evidence of association between LCE3C_LCE3B-del and psoriasis in Tunisian families. No epistasic effect was found between the deletion and PSORS1 locus. CONCLUSIONS: These findings indicate that the LCE3C_LCE3B-del does not contribute in a major way to psoriasis susceptibility in Tunisian families.
Assuntos
Cromossomos Humanos Par 1/genética , Proteínas Ricas em Prolina do Estrato Córneo/deficiência , Psoríase/genética , Deleção de Sequência , Adolescente , Adulto , Idoso , Criança , Cromossomos Humanos Par 6/genética , Proteínas Ricas em Prolina do Estrato Córneo/genética , Epistasia Genética , Saúde da Família , Feminino , Predisposição Genética para Doença/genética , Genótipo , Antígenos HLA-C/genética , Humanos , Mutação INDEL , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Psoríase/epidemiologia , Psoríase/etnologia , Tunísia/epidemiologia , Tunísia/etnologia , Adulto JovemRESUMO
BACKGROUND: Psoriasis is a relapsing chronic inflammatory skin disease affecting all population groups, with a peak prevalence of 3% in northern European and Scandinavian caucasians. Epidemiological studies have implicated a genetic component to psoriasis. In the past 12 years multiple genome-wide linkage analyses have identified putative susceptibility loci on several chromosomes, with a major locus in the major histocompatibility complex region. OBJECTIVES: To investigate the genetic basis of familial psoriasis in the Tunisian population using a genome-wide linkage scan in seven ultiplex psoriatic families from Tunisia. METHODS: Following single nucleotide polymorphism (SNP) genotyping on the Affymetrix 10K SNP array, we performed nonparametric linkage (NPL) multipoint analyses to identify genotypes and obtain evidence for linkage with psoriasis across the genome. RESULTS: No chromosomal region gave consistent evidence for linkage, providing evidence for genetic heterogeneity in Tunisian psoriasis families. Significant evidence for linkage of psoriasis to chromosome 2p12 was seen in one family. We also identified several regions of tentative psoriasis linkage on chromosomes 2q, 4q, 6p, 11q, 12q, 9q and 13q. One family exhibiting suggestive evidence for linkage to 17q25 (PSORS2) was identified and all affected members harboured a p.Gly117Ser mutation in CARD14 (caspase recruitment domain family, member 14), recently reported to lead to psoriasis in a large family from the U.S.A. CONCLUSIONS: Our results support the genetic heterogeneity of psoriasis in the Tunisian population, provide confirmatory evidence for a novel psoriasis locus at chromosome 2p12 and reveal a psoriasis family with a mutation at PSORS2.
Assuntos
Cromossomos Humanos Par 2/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Psoríase/genética , Adolescente , Adulto , Idoso , Proteínas Adaptadoras de Sinalização CARD , Criança , Feminino , Ligação Genética/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genótipo , Guanilato Ciclase , Humanos , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Linhagem , Tunísia , Adulto JovemRESUMO
Hereditary breast cancer accounts for 3-8% of all breast cancers, with mutations in the BRCA1 and BRCA2 genes responsible for up to 30% of these. To investigate the prevalence of BRCA1 and BRCA2 gene mutations in breast cancer patients with affected relatives in Tunisia, we studied 36 patients who had at least one first degree relative with breast and/or ovarian cancer Thirty-four 34 patients were suggestive of the BRCA1 mutation and two were suggestive of the BRCA2 mutation, based on the presence of male breast cancer detected in their corresponding pedigrees. Four mutations in BRCA1 were detected, including a novel frame-shift mutation (c.211dupA) in two unrelated patients and three other frameshift mutations--c.4041delAG, c.2551delG and c.5266dupC. Our study is the first to describe the c.5266dupC mutation in a non-Jewish Ashkenazi population. Two frameshift mutations (c.1309del4 and c.5682insA) were observed in BRCA2. Nineteen percent (7/36) of the familial cases had deleterious mutations of the BRCA1 or BRCA2 genes. Almost all patients with deleterious mutations of BRCA1 reported a family history of breast and/or ovarian cancer in the index case or in their relatives. Our data are the first to contribute to information on the mutation spectrum of BRCA genes in Tunisia, and we give a recommendation for improving clinical genetic testing policy.