RESUMO
Mutations in the UGT1A1 gene cause Crigler-Najjar syndrome (CN), which causes non-hemolytic unconjugated hyperbilirubinemia, and is categorized as CN1 and CN2 according to the severity of bilirubin levels. The UGT1A1 gene is responsible for encoding the liver enzyme uridine diphosphate-glucuronosyltransferase, UGT1A1. This protein adds glucuronic acid to unconjugated bilirubin in bilirubin metabolism to form conjugated bilirubin. CN2 occurs when UGT1A1 activity is low, while CN1 is the absence of UGT1A1 activity; therefore, the CN2 phenotype is not as severe as that of CN1. Here, we report a novel allele of compound heterozygous mutations in UGT1A1 in a Thai male infant with clinical symptoms of CN2. The patient's compound heterozygosity was composed of a novel mutation, c.1069-1070insC, and the c.1456T>G mutation. The novel c.1069-1070insC mutation generated a premature stop codon in exon 4 (p.R357Pfs*24). The healthy parents were heterozygous for the c.1069-1070insC mutation (father) and c.1456T>G missense mutation (mother). Our results suggest that compound heterozygosity of the novel c.1069-1070insC and c.1456T>G (c211 G >A) missense mutation in the UGT1A1 gene played a primary role in the development of CN2 unconjugated hyperbilirubinemia.
Assuntos
Síndrome de Crigler-Najjar/diagnóstico , Mutação da Fase de Leitura , Glucuronosiltransferase/genética , Mutação de Sentido Incorreto , Sequência de Bases , Síndrome de Crigler-Najjar/genética , Análise Mutacional de DNA , Éxons , Estudos de Associação Genética , Heterozigoto , Humanos , Lactente , Masculino , TailândiaRESUMO
Human uridine 5'-diphosphate-glucuronosyltransferases play a critical role in detoxification by conjugating bilirubin with glucoronic acid. Impaired or reduced enzymatic activity causes a spectrum of clinical disorders such as Crigler-Najjar syndrome type I (CN1), Crigler-Najjar syndrome type II, and Gilbert's syndrome. CN1 is a severe form of unconjugated hyperbilirubinemia caused by homozygous or compound heterozygous mutations in the gene for uridine 5'-diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1), resulting in complete loss of enzyme function. Here, we report a novel homozygous mutation of UGT1A1 in a female Thai infant who was diagnosed with CN1, and her parents were found to be heterozygous carriers. The patient was homozygous for the c.558C>A mutation, which resulted in a premature stop codon in exon 1. Her asymptomatic parents were carriers of the nonsense c.558C>A mutation. Our result suggests an important role for homozygous c.558C>A mutations in the UGT1A1 gene in the development of severe unconjugated hyperbilirubinemia.
Assuntos
Povo Asiático/genética , Códon de Terminação/genética , Síndrome de Crigler-Najjar/genética , Éxons/genética , Glucuronosiltransferase/genética , Mutação/genética , Sequência de Bases , Síndrome de Crigler-Najjar/fisiopatologia , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Recém-Nascido , Testes de Função Hepática , Imageamento por Ressonância Magnética , Dados de Sequência MolecularRESUMO
Crigler-Najjar syndrome is a rare autosomal recessive disease caused by mutations in the UGT1A1 gene. These mutations result in the deficiency of UGT1A1, a hepatic enzyme essential for bilirubin conjugation. This report describes the case of a 4-month-old boy with the cardinal symptoms of Crigler-Najjar syndrome type II. Molecular genetic analysis showed a homozygous UGT1A1 promoter mutation [A(TA)7TAA] and a heterozygous insertion of 1 adenosine nucleotide between positions 353 and 354 in exon 1 of UGT1A1 that caused a frameshift with a premature stop codon.
Assuntos
Bilirrubina/genética , Síndrome de Crigler-Najjar/genética , Glucuronosiltransferase/genética , Regiões Promotoras Genéticas , Povo Asiático/genética , Bilirrubina/metabolismo , Códon sem Sentido/genética , Síndrome de Crigler-Najjar/patologia , Éxons , Mutação da Fase de Leitura , Heterozigoto , Homozigoto , Humanos , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Piperine, an amide isolated from Piper species (Piperaceae), has been reported to exhibit central nervous system depression, anti-pyretic and anti-inflammatory activity. Immunomodulatory and anti-tumor activity of piperine has been demonstrated in mouse carcinomas. However, there is little information available concerning the effect of piperine on humans. We evaluated the immunopharmacological activity of this compound in human immune cells. Human peripheral blood mononuclear cells (PBMCs) were exposed to piperine, and cell proliferation was determined by the MTS assay. Piperine significantly inhibited phytohemagglutinin-stimulated human PBMC proliferation after exposure for 72 h. This compound inhibited PBMC activity, with an IC(50) of 100.73 ± 11.16 µg/mL. Production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) was measured using an ELISA assay and RT-PCR. Piperine inhibited IL-2 and IFN-γ production in the PBMCs. RT-PCR data indicated that IL-2 and IFN-γ mRNA expression in PBMCs is suppressed by piperine. This compound significantly inhibited the production of these two cytokines by activated PBMCs in a dose-dependent manner. In conclusion, piperine appears to have potential as an immunomodulatory agent for immune system suppression.
Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Citocinas/biossíntese , Fatores Imunológicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/toxicidade , Benzodioxóis/toxicidade , Proliferação de Células/efeitos dos fármacos , Humanos , Fatores Imunológicos/toxicidade , Interferon gama/biossíntese , Interferon gama/genética , Interleucina-2/biossíntese , Interleucina-2/genética , Ativação Linfocitária/imunologia , Fito-Hemaglutininas/imunologia , Piperidinas/toxicidade , Alcamidas Poli-Insaturadas/toxicidade , RNA Mensageiro/metabolismoRESUMO
Human parechoviruses (HPeVs) are highly prevalent RNA viruses classified in the family Picornaviridae. Several antigenically distinct types circulate in human populations worldwide, whilst recombination additionally contributes to the genetic heterogeneity of the virus. To investigate factors influencing the likelihood of recombination and to compare its dynamics among types, 154 variants collected from four widely geographically separated referral centres (UK, The Netherlands, Thailand and Brazil) were typed by VP3/VP1 amplification/sequencing with recombination groups assigned by analysis of 3Dpol sequences. HPeV1B and HPeV3 were the most frequently detected types in each referral region, but with marked geographical differences in the frequencies of different recombinant forms (RFs) of types 1B, 5 and 6. HPeV1B showed more frequent recombination than HPeV3, in terms both of evolutionary divergence and of temporal/geographical indicators of population separation. HPeV1 variants showing between 10 and 20% divergence in VP3/VP1 almost invariably fell into different recombination groups, compared with only one-third of similarly divergent HPeV3 variants. Substitution rates calculated by beast in the VP3/VP1 region of HPeV1 and HPeV3 allowed half-lives of the RFs of 4 and 20 years, respectively, to be calculated, estimates fitting closely with their observed lifespans based on population sampling. The variability in recombination dynamics between HPeV1B and HPeV3 offers an intriguing link with their markedly different seasonal patterns of transmission, age distributions of infection and clinical outcomes. Future investigation of the epidemiological and biological opportunities and constraints on intertypic recombination will provide more information about its influence on the longer term evolution and pathogenicity of parechoviruses.