RESUMO

INTRODUCTION AND AIM: Type 3 Familial Partial Lipodystrophy (FPLD3) is a rare metabolic disease related to pathogenic PPARG gene variants. FPLD3 is characterized by a loss of fatty tissue in the upper and lower limbs, hips, and face. FPLD3 pathophysiology is usually associated with metabolic comorbidities such as type 2 diabetes, insulin resistance, hypertriglyceridemia, and liver dysfunction. Here, we clinically and molecularly characterized FPLD3 patients harboring novel PPARG pathogenic variants. MATERIALS AND METHODS: Lipodystrophy-suspected patients were recruited by clinicians from an Endocrinology Reference Center. Clinical evaluation was performed, biological samples were collected for biochemical analysis, and DNA sequencing was performed to define the pathogenic variants associated with the lipodystrophic phenotype found in our clinically diagnosed FPLD subjects. Bioinformatics predictions were conducted to characterize the novel mutated PPARγ proteins. RESULTS: We clinically described FPLD patients harboring two novel heterozygous PPARG variants in Brazil. Case 1 had the c.533T > C variant, which promotes the substitution of leucine to proline in position 178 (p.Leu178Pro), and cases 2 and 3 had the c.641 C > T variant, which results in the substitution of proline to leucine in the position 214 (p.Pro214Leu) at the PPARγ2 protein. These variants result in substantial conformational changes in the PPARγ2 protein. CONCLUSION: Two novel PPARG pathogenic variants related to FPLD3 were identified in a Brazilian FPLD cohort. These data will provide new epidemiologic data concerning FPLD3 and help understand the genotype-phenotype relationships related to the PPARG gene.

RESUMO

BACKGROUND AND AIMS: GPIHBP1 is an accessory protein of lipoprotein lipase (LPL) essential for its functioning. Mutations in the GPIHBP1 gene cause a deficit in the action of LPL, leading to severe hypertriglyceridemia and increased risk for acute pancreatitis. METHODS: We describe twelve patients (nine women) with a novel homozygous mutation in intron 2 of the GPIHBP1 gene. RESULTS: All patients were from the Northeastern region of Brazil and presented the same homozygous variant located in a highly conserved 3' splicing acceptor site of the GPIHBP1 gene. This new variant was named c.182-1G > T, according to HGVS recommendations. We verified this new GPIHBP1 variant's effect by using the Human Splicing Finder (HSF) tool. This mutation changes the GPIHBP1 pre-mRNA processing and possibly causes the skipping of the exon 3 of the GPIHBP1 gene, affecting almost 50% of the cysteine-rich Lys6 GPIHBP1 domain. Patients presented with severe hypertriglyceridemia (2351 mg/dl [885-20600]) and low HDL (18 mg/dl [5-41). Four patients (33%) had a previous history of acute pancreatitis. CONCLUSIONS: We describe a novel GPIHBP1 pathogenic intronic mutation of patients from the Northeast region of Brazil, suggesting the occurrence of a founder effect.

Assuntos

Hiperlipoproteinemia Tipo I , Pancreatite , Receptores de Lipoproteínas , Doença Aguda , Brasil , Feminino , Humanos , Hiperlipoproteinemia Tipo I/genética , Lipase Lipoproteica/genética , Masculino , Mutação , Pancreatite/genética , Receptores de Lipoproteínas/genética

RESUMO

Xeroderma pigmentosum complementation group A (XPA), is defective in xeroderma pigmentosum patients, causing pre-disposition to skin cancer and neurological abnormalities, which is not well understood. Here, we analyzed the XPA-deficient cells transcriptional profile under oxidative stress. The imbalance in of ubiquitin-proteasome system (UPS) gene expression was observed in XPA-deficient cells and the involvement of nuclear factor erythroid 2-related factor-2 (NFE2L2) was indicated. Co-immunoprecipitation assays showed the interaction between XPA, apurinic-apyrimidinic endonuclease 1 (APE1) and NFE2L2 proteins. Decreased NFE2L2 protein expression and proteasome activity was also observed in XPA-deficient cells. The data suggest the involvement of the growth arrest and DNA-damage-inducible beta (GADD45ß) in NFE2L2 functions. Similar results were obtained in xpa-1 (RNAi) Caenorhabditis elegans suggesting the conservation of XPA and NFE2L2 interactions. In conclusion, stress response activation occurs in XPA-deficient cells under oxidative stress; however, these cells fail to activate the UPS cytoprotective response, which may contribute to XPA patient's phenotypes.

Assuntos

Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteostase , Ubiquitina/metabolismo , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo , Células Cultivadas , Reparo do DNA , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Regulação para Baixo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Proteína de Xeroderma Pigmentoso Grupo A/genética

RESUMO

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare disease characterized by the near total absence of body fat at birth. BSCL etiology involves genetic variations in four different genes: AGPAT2, BSCL2, CAV1, and CAVIN1. The four different biochemical subtypes of the disease are distinguished depending on which gene is mutated. The diagnosis of lipodystrophy can be based on clinical criteria, but the gold standard remains genetic testing. Since many different mutations have already been correlated with the onset of the disease, the most indicative method is DNA sequencing. However, not all laboratories have the resources to perform sequencing. Thus, less expensive techniques that include narrow gene regions may be applied. In such cases, the target mutations to be tested must be carefully determined taking into account the frequency of the description of the mutations in the literature, the nationality of the patient, as well as their phenotype. This review considers the molecular basis of BSCL, including the manual count of the majority of mutations reported in the literature up to the year 2018. Ninety different genetic mutations in 332 cases were reported at different frequencies. Some mutations were distributed homogeneously and others were specific to geographic regions. Type 2 BSCL was mentioned most often in the literature (50.3% of the cases), followed by Type 1 (38.0%), Type 4 (10.2%), and Type 3 (1.5%). The mutations comprised frameshifts (34.4%), nonsense (26.6%), and missense (21.1%). The c.517dupA in the BSCL2 gene was the most frequent (13.3%), followed by c.589-2A>G in the AGPAT2 gene (11.5%), c.507_511delGTATC in the BSCL2 gene (9.7%), c.317-588del in the AGPAT2 gene (7.3%), and c.202C>T in the AGPAT2 gene (4.5%). This information should prove valuable for analysts in making decisions regarding the best therapeutic targets in a population-specific context, which will benefit patients and enable faster and less expensive treatment.

Assuntos

Lipodistrofia Generalizada Congênita/genética , Mutação/genética , Tecido Adiposo , Sequência de Aminoácidos , Animais , Sequência de Bases , Testes Genéticos/métodos , Humanos , Fenótipo

RESUMO

Oxidative stress generated during inflammation is associated with a wide range of pathologies. Resveratrol (RESV) displays anti-inflammatory and antioxidant activities, being a candidate for the development of adjuvant therapies for several inflammatory diseases. Despite this potential, the cellular responses induced by RESV are not well known. In this work, transcriptomic analysis was performed following lipopolysaccharide (LPS) stimulation of monocyte cultures in the presence of RESV. Induction of an inflammatory response was observed after LPS treatment and the addition of RESV led to decreases in expression of the inflammatory mediators, tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), without cytotoxicity. RNA sequencing revealed 823 upregulated and 2098 downregulated genes (cutoff ≥2.0 or ≤-2.0) after RESV treatment. Gene ontology analysis showed that the upregulated genes were associated with metabolic processes and the cell cycle, consistent with normal cell growth and differentiation under an inflammatory stimulus. The downregulated genes were associated with inflammatory responses, gene expression, and protein modification. The prediction of master regulators using the iRegulon tool showed nuclear respiratory factor 1 (NRF1) and GA-binding protein alpha subunit (GABPA) as the main regulators of the downregulated genes. Using immunoprecipitation and protein expression assays, we observed that RESV was able to decrease protein acetylation patterns, such as acetylated apurinic/apyrimidinic endonuclease-1/reduction-oxidation factor 1 (APE1/Ref-1), and increase histone methylation. In addition, reductions in p65 (nuclear factor-kappa B (NF-κB) subunit) and lysine-specific histone demethylase-1 (LSD1) expression were observed. In conclusion, our data indicate that treatment with RESV caused significant changes in protein acetylation and methylation patterns, suggesting the induction of deacetylase and reduction of demethylase activities that mainly affect regulatory cascades mediated by NF-кB and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. NRF1 and GABPA seem to be the main regulators of the transcriptional profile observed after RESV treatment.

Assuntos

Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Inflamação/genética , Monócitos/imunologia , Resveratrol/metabolismo , Acetilação , Citocinas/metabolismo , Fator de Transcrição de Proteínas de Ligação GA/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , NF-kappa B/metabolismo , Fator 1 Nuclear Respiratório/genética , Estresse Oxidativo , Análise de Sequência de RNA , Transdução de Sinais , Células U937

RESUMO

Seipin is a nonenzymatic protein encoded by the BSCL2 gene. It is involved in lipodystrophy and seipinopathy diseases. Named in 2001, all seipin functions are still far from being understood. Therefore, we reviewed much of the research, trying to find a pattern that could explain commonly observed features of seipin expression disorders. Likewise, this review shows how this protein seems to have tissue-specific functions. In an integrative view, we conclude by proposing a theoretical model to explain how seipin might be involved in the triacylglycerol synthesis pathway.

RESUMO

Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive disease characterized by the almost complete absence of adipose tissue. Due to a strong founder effect that resulted in a higher prevalence of BSCL in Rio Grande do Norte (RN), a state in northeastern Brazil, it has been essential that health professionals develop knowledge about this disease. Nurses are often the first point of contact with patients during health care assistance. The purpose of this study was to investigate the knowledge of these professionals about BSCL in two main hospitals in RN state. A questionnaire was applied to 199 nurses working in the Hospital Regional Mariano Coelho-HRMC (Regional Hospital Mariano Coelho), in Currais Novos-RN, and in the Hospital Universitário Onofre Lopes-HUOL (University Hospital Onofre Lopes), in Natal-RN. This study showed that most nursing professionals do not know about the disease, although they have already received patients with BSCL in those hospitals. The nurses from HRMC and HUOL lacked knowledge of BSCL and the healthcare of these patients requires immediate improvement. Significant efforts are required to close the gap between current and needed practice patterns.

Assuntos

Tecido Adiposo/fisiopatologia , Lipodistrofia Generalizada Congênita/epidemiologia , Lipodistrofia Generalizada Congênita/genética , Enfermeiras e Enfermeiros , Adulto , Brasil/epidemiologia , Educação em Enfermagem , Feminino , Efeito Fundador , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Lipodistrofia Generalizada Congênita/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários

RESUMO

INTRODUCTION: Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare autosomal recessive disease that affects the development of adipocytes and leads to an inability to store fat in adipocytes. This study aimed to evaluate the life expectancy and the causes of death of patients with BSCL. METHOD: We analyzed death certificates, and medical records of BSCL patients who died between 1997 and 2017. If the death certificate was incomplete or unavailable, we reviewed the medical records, and if they were not available too, we collected information from the patient's relatives to understand how the death happened. We calculated the potential years of life lost as a result of premature death. RESULTS: Twenty patients (12 female and 8 male) died between 1997 and 2017. The mean age at the time of death was 27.1±12.4 years (women 25.2±12.5 vs. men 29.9±12.6 years, p = 0.41). Life expectancy for the study population was 62.9±4.8 years. The potential number of years of life lost was 35.6±16.6 years. The causes of deaths were divided into three major groups: infections (7 patients, 35%), liver disease (7 patients, 35%), and other causes (acute pancreatitis, one patient; renal failure, three patients; sudden death/myocardial infarction, two patients). Three patients had pulmonary fibrosis. CONCLUSION: BSCL led to premature death, cutting the patients' lifespan by 30 or more years. The majority of these young patients died of liver disease or infection. Other studies are needed to understand better the mechanisms that predispose to infections, as well as to assess whether new therapies can alter the natural history of this disease.

Assuntos

Causas de Morte , Expectativa de Vida , Lipodistrofia Generalizada Congênita/mortalidade , Doenças Raras/mortalidade , Adolescente , Adulto , Feminino , Humanos , Infecções/mortalidade , Lipodistrofia Generalizada Congênita/complicações , Lipodistrofia Generalizada Congênita/genética , Hepatopatias/etiologia , Hepatopatias/mortalidade , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Pancreatite/mortalidade , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/mortalidade , Doenças Raras/complicações , Doenças Raras/genética , Insuficiência Renal/etiologia , Insuficiência Renal/mortalidade , Adulto Jovem

RESUMO

BACKGROUND: Berardinelli-Seip Congenital Lipodystrophy (BSCL) is a rare disease characterized by the almost complete absence of adipose tissue. Although a large number of BSCL cases was previously identified in Rio Grande do Norte (RN), a state in Northeast Brazil, its prevalence in RN regions and municipalities remains unknown. The purpose of this study was to better characterize the prevalence of BSCL in RN. METHODS: A descriptive study was conducted using secondary data obtained from the Association of Parents and People with BSCL of RN to determine its prevalence. The patients' socio-demographic characteristics and geolocalization were analyzed. RESULTS: We estimated a total of 103 BSCL cases in RN, resulting in a prevalence of 3.23 per 100,000 people. The Central Potiguar mesoregion, Seridó territory, Carnaúba dos Dantas and Timbaúba dos Batistas municipalities had a much higher prevalence of BSCL, with 20.56, 20.66, 498.05 and 217.85 per 100,000 people, respectively. CONCLUSIONS: Together, our results showed that BSCL is highly prevalent in RN and confirmed that our state has one of the highest prevalences of this lipodystrophy worldwide. More studies are still needed to better estimate the prevalence and incidence of BSCL in RN as well as in other states in Brazil. Trial registration Study Number 31809314.0.0000.5568.