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1.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
2.
Front Genet ; 10: 1005, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681433

RESUMO

Approximately 10% of breast cancer (BC) cases are hereditary BC (HBC), with HBC most commonly encountered in the context of hereditary breast and ovarian cancer (HBOC) syndrome. Although thousands of loss-of-function (LoF) alleles in over 20 genes have been associated with HBC susceptibility, the genetic etiology of approximately 50% of cases remains unexplained, even when polygenic risk models are considered. We focused on one of the least-studied European populations and applied whole-exome sequencing (WES) to 52 individuals from 17 Greek HBOC families, in which at least one patient was negative for known HBC risk variants. Initial screening revealed pathogenic variants in known cancer genes, including BARD1:p.Trp91* detected in a cancer-free individual, and MEN1:p.Glu260Lys detected in a BC patient. Gene- and variant-based approaches were applied to exome data to identify candidate risk variants outside of known risk genes. Findings were verified in a collection of Canadian HBOC patients of European ancestry (FBRCAX), in an independent group of Canadian BC patients (CHUM-BC) and controls (CARTaGENE), as well as in individuals from The Cancer Genome Atlas (TCGA) and the UK Biobank (UKB). Rare LoF variants were uncovered in MDM1 and NBEAL1 in Greek and Canadian HBOC patients. We also report prioritized missense variants SETBP1:c.4129G > C and C7orf34:c.248C > T. These variants comprise promising candidates whose role in cancer pathogenicity needs to be explored further.

3.
Curr Opin Lipidol ; 26(4): 317-24, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26103612

RESUMO

PURPOSE OF REVIEW: To summarize recent epidemiological, preclinical and clinical studies on the effects of Roux-en-Y-gastric bypass (RYGBP) surgery on cardiovascular risk factors and the underlying mechanisms. RECENT FINDINGS: Although RYGBP has mechanical effects on the gastrointestinal tract, the reduced gastric pouch and intestinal calorie absorption cannot fully explain the metabolic improvements. SUMMARY: Obesity predisposes to cardiovascular risk factors such as dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and hypertension. In contrast to the limited success of pharmacological and lifestyle interventions, RYGBP induces sustained weight loss, metabolic improvements and decreases morbidity/mortality. In line, RYGBP reduces cardiovascular risk factors. Although the mechanisms are not entirely understood, RYGBP induces complex changes in the gut affecting other organs through endocrine and metabolic signals from the intestine to all key metabolic organs, which can link RYGBP and decreased cardiovascular risk. Here, we discuss the roles of changes in lipid absorption and metabolism, bile acid metabolism, gut hormones and the microbiote as potential mechanisms in the decreased cardiovascular risk and metabolic improvement after RYGBP.


Assuntos
Cirurgia Bariátrica , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Lipoproteínas/metabolismo , Animais , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/prevenção & controle , Humanos , Fatores de Risco
4.
Surg Obes Relat Dis ; 10(4): 679-83, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25224167

RESUMO

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery improves glucose control in most but not all patients with type 2 diabetes mellitus (T2 DM). Transcription factor 7-like 2 (TCF7 L2) gene variation (rs7903146, C: wild-type allele, T: risk-allele) is the strongest contributor to T2 DM risk. Until now, there are no studies investigating gene interactions with changes of glycemia in obese patients with T2 DM after RYGB. The objective of this study was to assess the effect of TCF7 L2 genotype on RYGB-induced changes in glucose homeostasis in 99 obese patients with T2 DM at 1-year follow-up. METHODS: Body mass index (BMI) and fasting blood glucose (FBG) were measured before and 1, 3, 6, and 12 months after RYGB. Genotyping was performed with TaqMan technology. The effect of the interaction between TCF7 L2 genotype and postoperative time on BMI and FBG changes was analyzed with a linear mixed model. RESULTS: Preoperatively, there was no difference in BMI, FBG, and other diabetes associated traits between homozygous (CC) (n = 49) and heterozygous (CT) or homozygous (TT) T risk-allele carriers (n = 50). One year after RYGB, 48 out of 99 patients had glycosylated hemoglobin (HbA1 c) lower than 6.5% in absence of any antidiabetic medication. BMI decreased similarly in both groups (P = .769, genotype-time interaction), however, the decrease in FBG over time was lower in T risk-allele carriers (P = .016, genotype-time interaction). At 1 year, FBG was 6.42 ± 2.98 mmol/L in CT/TT versus 5.36 ± 0.98 mmol/L in CC (P = .022, t test). CONCLUSION: TCF7 L2 gene variation affected the decrease of FBG after RYGB in obese patients with T2 DM, independently of weight loss.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Derivação Gástrica , Obesidade Mórbida/sangue , Obesidade Mórbida/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/cirurgia , Polimorfismo Genético/genética , Fatores de Tempo , Perda de Peso , Adulto Jovem
5.
Obesity (Silver Spring) ; 20(11): 2278-82, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22447289

RESUMO

Melanocortin-4 receptor (MC4R) loss-of-function mutations are the commonest genetic cause of human monogenic obesity, so far. The contribution of MC4R coding mutations to severe obesity in the high-obesity prone Greek population has not been investigated to date. We determined the MC4R coding sequence of 510 obese and 469 lean control subjects of Greek origin, and we estimated the prevalence and the penetrance on obesity of MC4R loss-of-function mutations. The functional impact of novel nonsynonymous variants detected was investigated in vitro. We found two novel synonymous mutations (L23L and I102I), four nonsynonymous mutations (T112M, S127L, N274S, and S295L), and two polymorphisms (V103I and I251L) previously described in literature. We also detected a novel mutation (L207V) in a severely obese 69-year-old female patient, although the mutation did not cosegregate with obesity in the corresponding pedigree and had no functional consequences on MC4R protein function. Loss-of-function mutations represented 75% of all nonsynonymous rare mutations identified among lean carriers and only 25% among obese subjects (P = 0.0001). The prevalence of loss-of-function mutations was lower in the obese group than in lean control subjects (0.20 vs. 0.64%) but this difference was not significant. Therefore, the estimated penetrance of deleterious MC4R mutations was very low (6.3%) in heterozygous Greek carriers of MC4R loss-of-function mutations. Our data suggest that MC4R loss-of-function mutations are rare in the Greek population. MC4R genetic deficiency is unlikely to explain the high propensity to develop severe obesity in this specific population.


Assuntos
Mutação de Sentido Incorreto , Obesidade Mórbida/genética , Receptor Tipo 4 de Melanocortina/genética , Idoso , Distribuição da Gordura Corporal , Estudos de Casos e Controles , Feminino , Grécia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/epidemiologia , Linhagem , Fenótipo , Receptor Tipo 4 de Melanocortina/deficiência , Análise de Sequência , Transdução de Sinais
6.
Nature ; 483(7389): 350-4, 2012 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-22343897

RESUMO

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.


Assuntos
Obesidade/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Sinalização do Cálcio , Diferenciação Celular , Análise Mutacional de DNA , Dieta Hiperlipídica , Metabolismo Energético , Europa (Continente)/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Éxons/genética , Fígado Gorduroso/complicações , Fígado Gorduroso/genética , Regulação da Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Intolerância à Glucose/complicações , Humanos , Insulina/metabolismo , Resistência à Insulina , Lipogênese , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Mutação/genética , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , Receptores Acoplados a Proteínas-G/deficiência , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais/genética
7.
Obesity (Silver Spring) ; 20(2): 389-95, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21720444

RESUMO

Twenty-four single-nucleotide polymorphisms (SNPs) have been reproducibly associated with obesity. We performed a follow-up study for obesity in the Greek adult population. A total of 510 obese and 469 lean adults were genotyped for 24 SNPs. We tested the association with obesity status using logistic regression and we evaluated the combined genetic risk of 24 SNPs by calculating the area under the receiver-operating characteristic (ROC) curves. We nominally replicated the association with obesity (BMI ≥30 kg/m(2)) of six SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci (1.28 ≤ odds ratio (OR) ≤ 1.35; 0.004 ≤ P ≤ 0.043). The discrimination ability for obesity was slightly stronger (P = 9.59 × 10(-6)) when the genetic information of the 24 SNPs was added to nongenetic risk factors (area under the curve (AUC) = 0.722) in comparison with nongenetic factors analyzed alone (AUC = 0.685). Our data suggest that SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci contribute to obesity risk in the Greek population.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Membrana/genética , Neuropeptídeos/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases/genética , Proteínas/genética , Receptor Tipo 4 de Melanocortina/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Proteínas de Ligação ao Cálcio , Estudos de Casos e Controles , Feminino , Seguimentos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Grécia/epidemiologia , Humanos , Masculino , Proteínas dos Microfilamentos , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fatores de Risco
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