Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions including generalized pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustular eruption. We identified two unreported IL36RN homozygous mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) in patients with familial generalized pustular psoriasis. We analyzed the impact of a spectrum of IL36RN mutations on IL-36 receptor antagonist protein by using site-directed mutagenesis and expression in HEK293T cells. This enabled us to differentiate null mutations with complete absence of IL-36 receptor antagonist (the two previously unreported mutations, c.80T>C/p.Leu27Pro, c.28C>T/p.Arg10X, c.280G>T/p.Glu94X, c.368C>G/p.Thr123Arg, c.368C>T/p.Thr123Met, and c.227C>T/p.Pro76Leu) from mutations with decreased (c.95A>G/p.His32Arg, c.142C>T/p.Arg48Trp, and c.308C>T/p.Ser113Leu) or unchanged (c.304C>T/p.Arg102Trp and c.104A>G/p.Lys35Arg) protein expression. Functional assays measuring the impact of mutations on the capacity to repress IL-36-dependent activation of the NF-κB pathway showed complete functional impairment for null mutations, whereas partial or no impairment was observed for other mutations considered as hypomorphic. Finally, null mutations were associated with severe clinical phenotypes (generalized pustular psoriasis, acute generalized exanthematous pustular eruption), whereas hypomorphic mutations were identified in both localized (palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) and generalized variants. These results provide a preliminary basis for genotype-phenotype correlation in patients with deficiency of the IL-36Ra (DITRA), and suggest the involvement of other factors in the modulation of clinical expression.
ABSTRACT. The association between the single nucleotide polymorphism rs762551 in the cytochrome P450 family 1, subfamily A2 gene (CYP1A2) and caffeine consumption remains controversial. We conducted a metaanalysis to clarify this potential association. Twelve studies were selected from articles retrieved from the and Google Scholar databases, and the data were analyzed to determine the odds ratio (OR) of genotypes AA (conferring fast caffeine metabolism) vs AC + CC (conferring slow caffeine metabolism). Comparisons were made between 6161 high caffeine consumers and 3219 low caffeine consumers. The overall analysis showed a significant association between genotype AA and coffee intake [OR = 1.13, 95% confidence interval (CI) = 1.03-1.24; Q = 19.23, P = 0.06; I 2 = 43%]. In subgroup analyses, the association was also found within male, younger, and Caucasian subjects (OR = 1.21, 95%CI = 1.08-1.35; OR = 1.71, 95%CI = 1.18-2.48; OR = 1.29, 95%CI = 1.12-1.49, respectively) but not in female, older, and Asian subjects (OR = 0.98, 95%CI = 0.83-1.15; OR = 0.83, 95%CI = 0.56-1.22; OR = 0.91, 95%CI = 0.71-1.17, respectively). Therefore, the rs762551 AA genotype may lead to higher coffee intake, especially in males, younger age groups, and individuals of Caucasian ethnicity. Our data highlight the need to test other CYP1A2 polymorphisms showing significance in genome-wide association studies to clarify the association with caffeine intake in the Asian population.
BackgroundBrugada syndrome (BrS) is a rare inherited cardiac arrhythmia associated with a high risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). BrS is characterized by coved-type ST-segment elevation in the right precordial leads (V1-V3). Mutations in SCN5A gene coding for the α-subunit of the NaV1.5 cardiac sodium channel are identified in 15–30% of BrS cases. Genetic testing of BrS patients generally involves sequencing of the protein-coding portions and flanking intronic regions of SCN5A. This excludes the 5′UTR and 3′UTR from the routine genetic testing.MethodsWe here screened the coding sequence, the flanking intronic regions as well as the 5′ and 3′UTR regions of SCN5A gene and further five candidate genes (GPD1L, SCN1B, KCNE3, SCN4B, and MOG1) in a Tunisian family diagnosed with BrS.ResultsA new SCN5A-Q1000K mutation was identified along with two common polymorphisms (H558R and D1819). Multiple genetic variants were identified on the SCN5A 3′UTR, one of which is predicted to create additional microRNA binding site for miR-1270. Additionally, we identified the hsa-miR-219a-rs107822. No relevant coding sequence variant was identified in the remaining studied candidate genes.ConclusionsThe absence of genotype-phenotype concordance within all the identified genetic variants in this family gives extra evidences about the complexity of the disease and suggests that the occurrence and prognosis of BrS is most likely controlled by a combination of multiple genetic factors, rather than a single variant. Most SCN5A variants were localized in non-coding regions hypothesizing an impact on the miRNA-target complementarities.
Brugada syndrome (BrS) is an autosomal-dominant genetic cardiac disorder caused in 18-30 % of the cases by SCN5A gene mutations and manifested by an atypical right bundle block pattern with ST segment elevation and T wave inversion in the right precordial leads. The syndrome is usually detected after puberty. The identification of BrS in pediatric patients is thus a rare occurrence, and most of the reported cases are unmasked after febrile episodes. Usually, having a family history of sudden death represents the first reason to perform an ECG in febrile children. However, this practice makes the sporadic cases of cardiac disease and specially the asymptomatic ones excluded from this diagnosis. Here, we report a sporadic case of a 2-month-old male patient presented with vaccination-related fever and ventricular tachycardia associated with short breathing, palpitation and cold sweating. ECG changes were consistent with type 1 BrS. SCN5A gene analysis of the proband and his family revealed a set of mutations and polymorphisms differentially distributed among family members, however, without any clear genotype-phenotype correlation. Based on our findings, we think that genetic testing should be pursued as a routine practice in symptomatic and asymptomatic pediatric cases of BrS, with or without family history of sudden cardiac death. Similarly, our study suggests that pediatrician should be encouraged to perform an ECG profiling in suspicious febrile children and quickly manage fever since it is the most important factor unmasking BrS in children.
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