RESUMO
Cerebrotendinous Xanthomatosis (CTX), a rare lipid storage disorder, is caused by recessive loss-of-function mutations of the 27-sterol hydroxylase (CYP27A1), producing an alteration of the synthesis of bile acids, with an accumulation of cholestanol. Clinical characteristics include juvenile cataracts, diarrhea, tendon xanthomas, cognitive impairment and other neurological manifestations. Early diagnosis is critical, because treatment with chenodeoxycholic acid may prevent neurological damage. We studied the CYP27A1 gene in two Chilean CTX patients by sequencing its nine exons, exon-intron boundaries, and cDNA from peripheral blood mononuclear cells. Patient 1 is a compound heterozygote for the novel substitution c.256-1G > T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the previously-known pathogenic mutation c.1183C > T (p.Arg395Cys). Patient 2 is homozygous for the novel mutation c.1185-1G > A that causes exon 7 skipping and the generation of a premature stop codon in exon 8, leading to the loss of the crucial adrenoxin binding domain of CYP27A1.
RESUMO
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, caused by genetic deficiency of the 27-hydroxylase enzyme (encoded by CYP27A1). It plays a key role in cholesterol metabolism, especially in bile acid synthesis and in the 25-hydroxylation of vitamin D3 in the liver. Its deficiency causes reduced bile acid synthesis and tissue accumulation of cholestanol. Clinical manifestations are related to the presence of cholestanol deposits and include tendon xanthomas, premature cataracts, chronic diarrhea, progressive neurologic impairment and less frequently coronary heart disease, early onset osteoporosis and abnormalities in the optic disk and retina. An early diagnosis and treatment with quenodeoxycholic acid may prevent further complications, mainly neurological manifestations. This review summarizes cholesterol metabolism related to bile acid synthesis, physiopathology, biochemistry and treatment of cerebrotendinous xanthomatosis.
Assuntos
Xantomatose Cerebrotendinosa , Ácido Quenodesoxicólico/uso terapêutico , Diagnóstico Precoce , Humanos , Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/tratamento farmacológico , Xantomatose Cerebrotendinosa/genética , Xantomatose Cerebrotendinosa/fisiopatologiaRESUMO
BACKGROUND: Metabolic Syndrome (MS) is highly prevalent among obese children and adolescents and is considered a predictor for the development of type 2 diabetes mellitus and cardiovascular disease. Obesity is associated with an increase in circulating levels of interleukins 6 (IL6) and 18 (IL18), which in turn would depend on polymorphisms of IL6, IL6R and IL18 genes. AIM: To evaluate the association between genetic polymorphisms of IL6 (rs1800795, rs1800796 and rs1800797), IL6R (rs2228145) and IL18 (rs360719, rs187238 and rs204355) and MS and/or its components in a sample of Chilean obese children. PATIENTS AND METHODS: These polymorphisms were genotyped in 259 obese children aged 10 ± 2 years with a body mass index of 26.1 ± 4.1 kg/m². Sixty eight had metabolic syndrome (26.3%). The association of their alleles, genotypes and haplotypes with the MS and its components was assessed. RESULTS: IL6, IL6R and IL18 variants showed no association with SM nor with any of the phenotypes that compose it. However, IL18 haplotypes (rs360719-rs187238-rs204355) TCT and CGT were associated with triglycerides ≤ 110 mg/dL and HDL < 40 mg/dL, respectively. CONCLUSIONS: IL6 and IL6R variants are not associated with MS or with any of its phenotypes. Although an association between IL18 haplotypes and certain MS component has been detected herein, it is necessary to replicate our findings in independent studies due to the low frequency of these allele combinations detected in our sample.
Assuntos
Interleucina-18/genética , Interleucina-6/genética , Síndrome Metabólica/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina-6/genética , Índice de Massa Corporal , Criança , Chile , Estudos Transversais , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , MasculinoRESUMO
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, caused by genetic deficiency of the 27-hydroxylase enzyme (encoded by CYP27A1). It plays a key role in cholesterol metabolism, especially in bile acid synthesis and in the 25-hydroxylation of vitamin D3 in the liver. Its deficiency causes reduced bile acid synthesis and tissue accumulation of cholestanol. Clinical manifestations are related to the presence of cholestanol deposits and include tendon xanthomas, premature cataracts, chronic diarrhea, progressive neurologic impairment and less frequently coronary heart disease, early onset osteoporosis and abnormalities in the optic disk and retina. An early diagnosis and treatment with quenodeoxycholic acid may prevent further complications, mainly neurological manifestations. This review summarizes cholesterol metabolism related to bile acid synthesis, physiopathology, biochemistry and treatment of cerebrotendinous xanthomatosis.
Assuntos
Humanos , Xantomatose Cerebrotendinosa , Ácido Quenodesoxicólico/uso terapêutico , Diagnóstico Precoce , Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/tratamento farmacológico , Xantomatose Cerebrotendinosa/genética , Xantomatose Cerebrotendinosa/fisiopatologiaRESUMO
Background: Metabolic Syndrome (MS) is highly prevalent among obese children and adolescents and is considered a predictor for the development of type 2 diabetes mellitus and cardiovascular disease. Obesity is associated with an increase in circulating levels of interleukins 6 (IL6) and 18 (IL18), which in turn would depend on polymorphisms of IL6, IL6R and IL18 genes. Aim: To evaluate the association between genetic polymorphisms of IL6 (rs1800795, rs1800796 and rs1800797), IL6R (rs2228145) and IL18 (rs360719, rs187238 and rs204355) and MS and/or its components in a sample of Chilean obese children. Patients and Methods: These polymorphisms were genotyped in 259 obese children aged 10 ± 2 years with a body mass index of 26.1 ± 4.1 kg/m². Sixty eight had metabolic syndrome (26.3%). The association of their alleles, genotypes and haplotypes with the MS and its components was assessed. Results: IL6, IL6R and IL18 variants showed no association with SM nor with any of the phenotypes that compose it. However, IL18 haplotypes (rs360719-rs187238-rs204355) TCT and CGT were associated with triglycerides ≤ 110 mg/dL and HDL < 40 mg/dL, respectively. Conclusions: IL6 and IL6R variants are not associated with MS or with any of its phenotypes. Although an association between IL18 haplotypes and certain MS component has been detected herein, it is necessary to replicate our findings in independent studies due to the low frequency of these allele combinations detected in our sample.
Assuntos
Criança , Feminino , Humanos , Masculino , /genética , /genética , Síndrome Metabólica/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , /genética , Índice de Massa Corporal , Chile , Estudos Transversais , Frequência do Gene , Genótipo , HaplótiposRESUMO
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme reduction of white adipose tissue (WAT) mass. CGL type 1 is the most frequent form and is caused by mutations in AGPAT2. Genetic and clinical studies were performed in two affected sisters of a Chilean family. These patients have notoriously dissimilar metabolic abnormalities that correlate with differential levels of circulating leptin and soluble leptin receptor fraction. Sequencing of AGPAT2 exons and exon-intron boundaries revealed two homozygous mutations in both sisters. Missense mutation c.299G>A changes a conserved serine in the acyltransferase NHX4D motif of AGPAT2 (p.Ser100Asn). Intronic c.493-1G>C mutation destroy a conserved splicing site that likely leads to exon 4 skipping and deletion of whole AGPAT2 substrate binding domain. In silico protein modeling provided insights of the mechanisms of lack of catalytic activity owing to both mutations.
Assuntos
Aciltransferases/genética , Predisposição Genética para Doença/genética , Lipodistrofia Generalizada Congênita/genética , Mutação , Irmãos , Aciltransferases/química , Aciltransferases/metabolismo , Adulto , Sequência de Bases , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Leptina/sangue , Leptina/metabolismo , Lipodistrofia Generalizada Congênita/sangue , Lipodistrofia Generalizada Congênita/metabolismo , Modelos Moleculares , Fenótipo , Estrutura Terciária de Proteína , Receptores para Leptina/metabolismoRESUMO
To study the association between the polymorphisms Arg462Gln and Asp541Glu from the RNASEL gene (1q25), and the polymorphisms rs620861, rs1447295, rs6983267, rs7837328 from the chromosome 8q24 with the risk of presenting prostate cancer (PCa) and its clinical characteristics in a Hispanic (Chilean) population. The study was performed on 21 control patients and 83 patients diagnosed with PCa. Polymorphisms were analysed from blood samples through real-time PCR by using TaqMan probes, and the genetic analysis was performed with the SNPStats program. Also, a comparison was performed between clinical characteristics of PCa and the presence of the different polymorphism genotypes by using the Minitab software. There was a significant association between the genotype G/G from the polymorphism rs6983267 with an overall increased risk of PCa, in patients both with or without family history of PCa (OR = 4.47, 95% CI = 1.05-18.94, P = 0.034 and OR = 3.57, 95% CI = 0.96-13.35, P = 0.037, respectively). Regarding clinical parameters, patients carrying the genotype C/C from the polymorphism Asp541Glu had significantly higher prostate-specific antigen (PSA) levels than patients carrying the other genotypes (P = 0.034). Moreover, patients with the genotype G/G of rs6983267 had higher PSA levels (P = 0.024). The polymorphism rs6983267 from region 3 of the chromosome 8q24 appears to be a prominent risk factor for PCa and a biomarker for cancer aggressiveness in the group of patients who presented higher levels of PSA at the time of diagnosis.
Assuntos
Cromossomos Humanos Par 8/genética , Endorribonucleases/genética , Neoplasias da Próstata/genética , Idoso , Estudos de Casos e Controles , Chile , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Risco , Análise de Sequência de DNA , Carga TumoralRESUMO
OBJECTIVE: The aim of this study was to assess the association between melanocortin-4 receptor (MC4R) rs17782313 alleles with obesity and eating behavior scores in Chilean children. METHODS: A case-control study was conducted with 139 normal-weight and 238 obese children (ages 6-12 y). MC4R rs17782313 genotypes were determined by quantitative-polymerase chain reaction allelic-discrimination assays. Eating behavior scores were evaluated in a subset of participants using the Chilean version of the Child Eating Behavior Questionnaire (CEBQ). Additionally, five normal-weight C-allele carriers of rs17782313 were matched by sex, age, and body mass index (BMI) to five TT homozygous children to carry out the Eating in the Absence of Hunger (EAH) test. RESULTS: The frequency of the C-allele of MC4R rs17782313 was higher in the obese group than in the control group, without achieving statistical significance (odds ratio, 1.4; 95% confidence interval, 0.8-2.4; P = 0.16). CEBQ scores of "enjoyment of food" were higher (P = 0.04) and "satiety responsiveness" were lower (P = 0.02) in children with CC genotype than in those with TT genotype matched by sex, age, and BMI. In the EAH test, all five non-obese carriers of the C-allele (three CC and two CT) showed increased sweet snack consumption compared with five matched (by sex-age-BMI) non-carriers after a preload meal, without achieving statistical significance (P = 0.06). CONCLUSION: MC4R polymorphism rs17782313 may contribute to childhood obesity, affecting enjoyment of food, satiety responsiveness, and possibly eating in the absence of hunger.
Assuntos
Obesidade Infantil/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 4 de Melanocortina/genética , Alelos , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Comportamento Infantil , Comportamento Alimentar , Feminino , Genótipo , Humanos , Fome/fisiologia , Modelos Logísticos , Masculino , Saciação , Inquéritos e QuestionáriosRESUMO
Maternally Inherited Diabetes and Deafness (MIDD) is caused by mutations in mitochondrial DNA (mtDNA), mainly m.3243A>G. Severity, onset and clinical phenotype of MIDD patients are partially determined by the proportion of mutant mitochondrial DNA copies in each cell and tissue (heteroplasmy). The identification of MIDD allows a corred treatment with insulin avoiding drugs that may interfere with mitochondrial electrón chain transpon. We estimated the degree of heteroplasmy of the mutation m.3243A>G from blood, saliva, hair root and a muscle biopsy using quantitative PCR (qPCR) in a femóle adult patient. For this purpose, PCR producís were inserted in a vector creating plasmids with 3243A or G. Mutant and wild-type vectors were mixed in different proportions to créate a calibration curve used to interpólate heteroplasmy percentages with qPCR threshold cycles. The proportions of m.3243A>G heteroplasmy were 62% (muscle), 14% (saliva), 6% (blood leukocytes) and 3% in hair root. Quantitative analysis of heteroplasmy showed marked variations in different tissues (highest in muscle and lowest in blood). Given the relatively high heteroplasmy found in saliva, this type of biológical sample may represent an adequate non-invasive way for assessing the presence of m.3243A>G mutations in epidemiologic studies.
Assuntos
DNA Mitocondrial/genética , Surdez/genética , Diabetes Mellitus Tipo 2/genética , Mutação/genética , Surdez/diagnóstico , Surdez/patologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Doenças Mitocondriais , Fenótipo , Reação em Cadeia da Polimerase/métodosRESUMO
Maternally Inherited Diabetes and Deafness (MIDD) is caused by mutations in mitochondrial DNA (mtDNA), mainly m.3243A>G. Severity, onset and clinical phenotype of MIDD patients are partially determined by the proportion ofmutant mitochondrial DNA copies in each cell and tissue (heteroplasmy). The identification ofMIDD allows a corred treatment with insulin avoiding drugs that may interfere with mitochondrial electrón chain transpon. We estimated the degree of heteroplasmy ofthe mutation m.3243A>G from blood, saliva, hair root and a muscle biopsy using quantitative PCR (qPCR) in a femóle adult patient. For this purpose, PCR producís were inserted in a vector creatingplasmids with 3243A or G. Mutant and wild-type vectors were mixed in different proportions to créate a calibration curve used to interpólate heteroplasmy percentages with qPCR threshold cycles. The proportions of m.3243A>G heteroplasmy were 62% (muscle), 14% (saliva), 6% (blood leukocytes) and 3% in hair root. Quantitative analysis of heteroplasmy showed marked variations in different tissues (highest in muscle and lowest in blood). Given the relatively high heteroplasmy found in saliva, this type of biológical sample may represent an adequate non-invasive way for assessing the presence of m.3243A>G mutations in epidemiologic studies.
Assuntos
Feminino , Humanos , Pessoa de Meia-Idade , DNA Mitocondrial/genética , Surdez/genética , /genética , Mutação/genética , Surdez/diagnóstico , Surdez/patologia , /diagnóstico , /patologia , Fenótipo , Reação em Cadeia da Polimerase/métodosRESUMO
BACKGROUND: Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. METHODS: We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. RESULTS: A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. CONCLUSION: The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.
Assuntos
Apolipoproteínas A/genética , Consanguinidade , Hipertrigliceridemia/genética , Mutação , Apolipoproteína A-V , Chile , Feminino , Ligação Genética , Homozigoto , Humanos , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: Inadequate eating behavior and physical inactivity contribute to the current epidemic of childhood obesity. The aim of this study was to assess the association between eating behavior scores and childhood obesity in Chilean children. DESIGN AND METHODS: We recruited 126 obese, 44 overweight and 124 normal-weight Chilean children (6-12 years-old; both genders) according to the International Obesity Task Force (IOTF) criteria. Eating behavior scores were calculated using the Child Eating Behavior Questionnaire (CEBQ). Factorial analysis in the culturally-adapted questionnaire for Chilean population was used to confirm the original eight-factor structure of CEBQ. The Cronbach's alpha statistic (>0.7 in most subscales) was used to assess internal consistency. Non-parametric methods were used to assess case-control associations. RESULTS: Eating behavior scores were strongly associated with childhood obesity in Chilean children. Childhood obesity was directly associated with high scores in the subscales "enjoyment of food" (P < 0.0001), "emotional overeating" (P < 0.001) and "food responsiveness" (P < 0.0001). Food-avoidant subscales "satiety responsiveness" and "slowness in eating" were inversely associated with childhood obesity (P < 0.001). There was a graded relation between the magnitude of these eating behavior scores across groups of normal-weight, overweight and obesity groups. CONCLUSION: Our study shows a strong and graded association between specific eating behavior scores and childhood obesity in Chile.
Assuntos
Comportamento Infantil/psicologia , Comportamento Alimentar/psicologia , Obesidade/epidemiologia , Obesidade/psicologia , Estudos de Casos e Controles , Criança , Chile/epidemiologia , Ingestão de Alimentos , Feminino , Humanos , Masculino , Sobrepeso , SaciaçãoRESUMO
Germline mutations in BRCA1 account for a low proportion of hereditary cases in diverse populations. Several efforts have been made to find new genes involved in the inheritance of breast cancer with no success until today. The participation of BRCA1 in the development of breast cancer has been proposed in several studies where hypermethylation of its promoter and a decrease in expression has been reported for sporadic cases and one study on familial cases. To explore the participation of BRCA1 in hereditary carcinogenesis through a different mechanism than the inheritance of germline mutations, we studied the methylation status of its promoter in breast tumors, from patients previously screened for BRCA1/BRCA2 germline mutations. We also determined the presence of the BRCA1 protein in these tumors and correlated both events with tumor grade, hormone receptors and ERBB2 presence. Promoter hypermethylation of the BRCA1 gene was detected in 51% of our biopsies, among which 67% did not express the respective protein. This result leads us to suggest that hypermethylation could be considered as an inactivating mechanism for BRCA1 expression, either as a first or second hit. Moreover, a number of biopsies with absence of expression on BRCA1 showed negative detection of estrogen and progesterone receptors, a similar phenotype to BRCA1 mutated breast tumors.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Hereditariedade , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Sequência de Bases , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Dados de Sequência MolecularRESUMO
Besides BRCA1 and BRCA2, two genes accounting for a small proportion of breast cancer cases, ATM has been widely proposed as a low-penetrance susceptibility gene. Several nucleotide changes have been proposed to be associated with breast cancer, still remaining a high controversy in this sense. We screened the ATM gene in 94 breast cancer patients selected from 78 high-risk families, not presenting a mutation in BRCA1 or BRCA2. We found three novel allelic variants: IVS64 + 51delT and p.L752L, not showing association with hereditary breast cancer, and p.L694L found in one family in two breast cancer patients. Two amino acid substitutions p.S707P and p.F858L, previously reported to be associated with breast cancer, were present in our study in cases and controls, lacking of association with breast cancer. A positive association of c.5557G>A (p.D1853N) was found (OR 2.52, P = 0.008), when analyzed alone and in combination with an intronic variant IVS24-9delT (OR 3.97; P = 0.0003). We postulate that our discrepancies with other reports related to the associated ATM alleles to hereditary breast cancer, as well as discrepancies in the literature between other groups, could be explained by the diversity in the ethnic origins of families gathered in a sole study, and the selection of the control group. In relation to this issue, and based on genetic markers, we found that the Chilean group of breast cancer families in this study has a stronger European genetic component than our control sample selected randomly from the Chilean population.