RESUMEN

Background: There is a lack of information on the clinical and molecular presentation of familial partial lipodystrophy (FPLD), a rare genetic disorder characterized by partial subcutaneous fat loss. Objective: This study aimed to provide a comprehensive assessment of the clinical, metabolic, and genetic features of FPLD in the Brazilian population. Methods: In a multicenter cross-sectional investigation we evaluated patients with FPLD across five Brazilian reference centers for lipodystrophies. Diagnosis of FPLD was made by clinical evaluation and genetic confirmation. Data on genetic, clinical, and metabolic characteristics were captured. Statistical analysis involved the utilization of the Kruskal-Wallis test to identify differences. Results: The study included 106 patients with genetic confirmation of FPLD. The mean age was 44 ± 15 years, and they were predominantly female (78.3%). LMNA pathogenic variants were identified in 85.8% of patients, PPARG in 10.4%, PLIN1 in 2.8%, and MFN2 in 0.9%. Diabetes mellitus (DM) was highly prevalent (57.5%), affecting 54 females (50.9%). Median triglycerides levels were 199 mg/dL (54-2724 mg/dL), severe hypertriglyceridemia (≥ 500 mg/dL) was found in 34.9% and pancreatitis in 8.5%. Metabolic-associated fatty liver disease (MAFLD) was observed in 56.6%, and cardiovascular disease in 10.4%. The overall mortality rate was 3.8%, due to cardiovascular events. Conclusion: This study presents an extensive cohort of Brazilian patients with FPLD, predominantly DM with several multisystem complications. A comprehensive characterization of lipodystrophy syndromes is crucial for effective patient management and care.

Asunto(s)

Lipodistrofia Parcial Familiar , Humanos , Femenino , Masculino , Lipodistrofia Parcial Familiar/genética , Lipodistrofia Parcial Familiar/epidemiología , Adulto , Estudios Transversales , Persona de Mediana Edad , Brasil/epidemiología , Morbilidad , Lamina Tipo A/genética

RESUMEN

OBJECTIVE: To report the case of a girl presenting a severe phenotype of mandibuloacral dysplasia type A (MADA) characterized by prominent osteolytic changes and ectodermal defects, associated with a rare homozygous LMNA missense mutation (c.1579C>T). CASE DESCRIPTION: A 6-year-old girl was evaluated during hospitalization exhibiting the following dysmorphic signs: subtotal alopecia, dysmorphic facies with prominent eyes, marked micrognathia and retrognathia, small beaked nose, teeth crowding and thin lips, generalized lipodystrophy, narrow and sloping shoulders, generalized joint stiffness and bone reabsorption in the terminal phalanges. In dermatological examination, atrophic skin, loss of cutaneous elasticity, hyperkeratosis, dermal calcinosis, and hyperpigmented and hypochromic patches were observed. Radiology exams performed showed bilateral absence of the mandibular condyles, clavicle resorption with local amorphous bone mass confluence with the scapulae, shoulder joints with subluxation and severe bone dysplasia, hip dysplasia, osteopenia and subcutaneous calcifications. COMMENTS: MADA is a rare autosomal recessive disease caused by mutations in LMNA gene. It is characterized by craniofacial deformities, skeletal anomalies, skin alterations, lipodystrophy in certain regions of the body and premature ageing. Typical MADA is caused by the p.R527H mutation in the LMNA gene. However, molecular analysis performed from oral epithelial cells obtained from the patient showed the rare mutation c.1579C>T, p. R527C in the exon 9 of LMNA. This is the sixth family identified with this mutation described in the literature.

Asunto(s)

Lamina Tipo A , Mutación Missense , Fenotipo , Humanos , Femenino , Lamina Tipo A/genética , Niño , Mandíbula/anomalías , Mandíbula/diagnóstico por imagen , Lipodistrofia , Acroosteólisis

RESUMEN

Lipodystrophies are characterized by complete or selective loss of adipose tissue and can be acquired or inherited. Familial partial lipodystrophy (FPLD) is a hereditary lipodystrophy commonly caused by mutations in the LMNA gene. Herein, we report two cases of FPLD associated with podocytopathies. Patient 1 was diagnosed with FPLD associated with the heterozygous p.Arg482Trp variant in LMNA and had normal glucose tolerance and hyperinsulinemia. During follow-up, she developed nephroticrange proteinuria. Renal biopsy was consistent with minimal change disease. Patient 2 was diagnosed with FPLD associated with a de novo heterozygous p.Arg349Trp variant in LMNA. Microalbuminuria progressed to macroalbuminuria within 6 years and tonephrotic range proteinuria in the last year. He remained without diabetes and with hyperinsulinemia. Renal biopsy revealed focal segmental glomerulosclerosis not otherwise specified. This report provides further evidence of variable features of lipodystrophy associated with LMNA variants and the importance of long-term follow-up with evaluation of kidney dysfunction.

Asunto(s)

Lamina Tipo A , Lipodistrofia Parcial Familiar , Humanos , Lamina Tipo A/genética , Lipodistrofia Parcial Familiar/genética , Lipodistrofia Parcial Familiar/complicaciones , Femenino , Masculino , Adulto , Podocitos/patología , Mutación

RESUMEN

The clinical phenotype of LMNA-associated dilated cardiomyopathy (DCM) varies even among individuals who share the same mutation. LMNA encodes lamin AC, which interacts with the lamin-associated protein 2 alpha (LAP2α) encoded by the TMPO gene. The LAP2α/Arg690Cys polymorphism is frequent in Latin America and was previously found to disrupt LAP2α-Lamin AC interactions in vitro. We identified a DCM patient heterozygous for both a lamin AC truncating mutation (Ser431*) and the LAP2α/Arg690Cys polymorphism. We performed protein modeling and docking experiments, and used confocal microscopy to compare leukocyte nuclear morphology among family members with different genotype combinations (wild type, LAP2α Arg690Cys heterozygous, lamin AC/Ser431* heterozygous, and LAP2α Arg690Cys/lamin AC Ser431* double heterozygous). Protein modeling predicted that 690Cys destabilizes the LAP2α homodimer and impairs lamin AC-LAP2α docking. Lamin AC-deficient nuclei (Ser431* heterozygous) showed characteristic blebs and invaginations, significantly decreased nuclear area, and increased elongation, while LAP2α/Arg690Cys heterozygous nuclei showed a lower perimeter and higher circularity than wild-type nuclei. LAP2α Arg690Cys apparently attenuated the effect of LMNA Ser431* on the nuclear area and fully compensated for its effect on nuclear circularity. Altogether, the data suggest that LAP2α/Arg690Cys may be one of the many factors contributing to phenotype variation of LMNA-associated DCM.

Asunto(s)

Cardiomiopatía Dilatada , Timopoyetinas , Humanos , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/metabolismo , Lamina Tipo A/metabolismo , Leucocitos/metabolismo , Mutación , Mutación Missense , Proteínas Nucleares/genética

RESUMEN

Abstract Isolated left ventricular apical hypoplasia is a rare cardiomyopathy, with a broad range of clinical presentations. Since this entity was already described in association with osteomuscular diseases, mutation in the Lamin A/C gene has been regarded as a possible cause of this disease. This study describes the case of an asymptomatic teenager with isolated left ventricular apical hypoplasia and arthrogriposis but with no mutations in the entire Lamin A/C gene.

Asunto(s)

Humanos , Masculino , Adolescente , Lamina Tipo A/genética , No Compactación Aislada del Miocardio Ventricular/fisiopatología , Artrogriposis , Lamina Tipo A/deficiencia , No Compactación Aislada del Miocardio Ventricular/diagnóstico , No Compactación Aislada del Miocardio Ventricular/etiología

RESUMEN

El Síndrome de Progeria de Hutchinson-Gilford es una enfermedad que se caracteriza por el envejecimiento prematuro en niños, debido a una mutación en el gen de Lámina tipo A involucrado en la mitosis celular. En el presente trabajo, con el objetivo de dar difusión al conocimiento de esta enfermedad, se señalan los procesos involucrados en su desarrollo, así como los avances científicos y el alcance de nuevas ventanas terapéuticas. La revisión se realizó consultando artículos en español e inglés empleando los motores de búsqueda Pubmed y Google Académico. La actualización del personal de salud sobre las enfermedades genéticas congénitas es de vital importancia para mejorar su detección, atención y manejo(AU)

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Hutchinson-Gilford Progeria Syndrome is a disease characterized by premature aging in children, due to a mutation in the Lamina type A, gene involved in cellular mitosis. In the present work, with the aim of spreading the knowledge of this disease, the processes involved in its development, the scientific advances, and the scope of new therapeutic treatments were summarized. The review was carried out by consulting articles in Spanish and English using the Pubmed and Google Academic search engines. The updating of health personnel on congenital genetic diseases is of vital importance to improve their detection, care and management(EU)

Asunto(s)

Humanos , Enfermedades Genéticas Congénitas , Envejecimiento Prematuro , Síndrome de Cockayne/fisiopatología , Lamina Tipo A

Asunto(s)

Tumores del Estroma Gastrointestinal/genética , Proteínas de Fusión Oncogénica/genética , Receptor trkA/genética , Neoplasias del Recto/genética , Prolapso Rectal/etiología , Biopsia , Colonoscopía , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Lamina Tipo A/genética , Masculino , Proctectomía , Neoplasias del Recto/diagnóstico , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Recto/diagnóstico por imagen , Recto/patología , Recto/cirugía , Adulto Joven

RESUMEN

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of nonischemic heart failure and death in young adults. Next generation sequencing (NGS) has become part of the diagnostic workup in idiopathic and familial DCM. More than 50 DCM genes have been identified, revealing great molecular heterogeneity and variable diagnostic yield. Interpretation of variant pathogenicity is challenging particularly in underrepresented populations, as pathogenic variant databases include studies mainly from European/Caucasian populations. To date, no studies on genomic diagnosis of DCM have been conducted in Mexico. METHODS: We recruited 55 unrelated DCM patients, 22 familial (F-DCM), and 33 idiopathic (I-DCM), and performed site-directed NGS seeking causal mutations. Diagnostic yield was defined as the proportion of individuals with at least one pathogenic (P) or likely pathogenic (LP) variant in DCM genes. RESULTS: Overall diagnostic yield was 47.3%, and higher in F-DCM (63.6%) than in I-DCM (36.4%, p = 0.047). Overall, NGS disclosed 41 variants of clinical interest (61.0% novel), 27 were classified as P/LP and 14 of unknown clinical significance. Of P/LP variants, 10 were A-band region TTN truncating variants, five were found in DSP (18.5%), five in MYH7 (18.5%), two in LMNA (7.4%), and one in RBM20, ABCC9, FKTN, ACTA1, and TNNT2. NGS findings suggested autosomal recessive inheritance in three families, two with DSP loss of function mutations in affected individuals. The increasing number of mutation reports in DCM, increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of DCM-related proteins, the recent refinement ACMG/ClinGen Guidelines, and co-segregation analysis in DCM families helped increase the diagnostic yield. CONCLUSION: This is the first NGS study performed in a group of Mexican DCM patients, contributing to understand the mutational spectrum and complexity of DCM molecular diagnosis.

Asunto(s)

Cardiomiopatía Dilatada/genética , Frecuencia de los Genes , Adolescente , Adulto , Miosinas Cardíacas/genética , Conectina/genética , Desmoplaquinas/genética , Femenino , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lamina Tipo A/genética , Masculino , México , Cadenas Pesadas de Miosina/genética , Análisis de Secuencia de ADN

RESUMEN

The LMNA gene is associated to a huge broad of phenotypes, including congenital Emery-Dreifuss muscular dystrophy and late-onset LMNA-related muscular dystrophy. In these forms, muscle weakness, contractures, and cardiac impairment are common. In an autosomal dominant pedigree including 5 affected patients, NGS molecular analysis performed in 6 relatives identifies the heterozygous c.1129C>T p.Arg377Cys variant in the exon 6 of the LMNA gene in three of them. Clinical, laboratorial, imaging investigation of these affected patients showed a significant clinical variability: the father presented subclinical imaging muscular dystrophy masqueraded as radiculopathy. One of his sons presented cardiac arrhythmia, muscular weakness, elbow contractures, and intranuclear pseudoinclusions on muscle biopsy. A second son presented only decreased tendon reflexes. Two other brothers presenting myalgia and cramps were not carriers of the same mutation in the LMNA gene. Early diagnosis, considering these variable phenotype and genotype, is important for genetic counseling, as well as cardiac, and rehabilitation management.

Asunto(s)

Variación Biológica Poblacional , Lamina Tipo A/genética , Distrofia Muscular de Emery-Dreifuss/patología , Linaje , Adulto , Diagnóstico Diferencial , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular de Emery-Dreifuss/diagnóstico por imagen , Distrofia Muscular de Emery-Dreifuss/genética , Mutación Missense

RESUMEN

BACKGROUND: Anthracyclines are highly effective anticancer medication prescribed for the treatment of breast cancer. Nevertheless, the use of anthracyclines as chemotherapeutic agents involves a risk for development of cardiac toxicity which may cause restrictive and dilated cardiomyopathy. Currently, genetic predisposition is not considered as a risk factor for cardiotoxicity associated to the use of anthracyclines. CASE PRESENTATION: We report the case of a 37-years old Panamanian female patient diagnosed with breast cancer who developed clinical signs of severe heart failure after treatment with doxorubicin. A diagnosis of anthracycline induced cardiomyopathy was made and treatment was initiated accordingly. A whole exome sequencing study performed to the patient showed the presence of a missense mutation in LMNA gene, which codifies for lamin A/C. Our results points to a correlation between the LMNA variant and the anthracycline cardiotoxicity developed by the woman. Improvement of the clinical symptoms and the left ventricle ejection fraction was observed after proper treatment. CONCLUSIONS: This case report suggests for the first time a potential genetic predisposition for anthracyclines induced cardiomyopathy in patients with mutations in LMNA gene. Perhaps chemotherapies accelerate or deliver the "second-hit" in the development of DCM in patients with genetic mutations. More data is needed to understand the contribution of LMNA variants that predispose to DCM in patients receiving cardiotoxic therapies.

Asunto(s)

Antibióticos Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Cardiomiopatía Dilatada/inducido químicamente , Cardiomiopatía Dilatada/genética , Doxorrubicina/efectos adversos , Lamina Tipo A/genética , Mutación Missense , Variantes Farmacogenómicas , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Antihipertensivos/uso terapéutico , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/tratamiento farmacológico , Cardiotoxicidad , Diuréticos/uso terapéutico , Femenino , Predisposición Genética a la Enfermedad , Humanos , Factores de Riesgo , Resultado del Tratamiento

RESUMEN

Familial partial lipodystrophy type 2 (FPLD2) is characterized by insulin resistance, adipose atrophy of the extremities and central obesity. Due to the resemblance with Cushing's syndrome, we hypothesized a putative role of glucocorticoid in the pathogenesis of metabolic abnormalities in FPLD2. OBJECTIVE: To evaluate the phenotypic heterogeneity and glucocorticoid sensitivity in FPLD2 patients exhibiting the p.R482W or p.R644C LMNA mutations. DESIGN, PATIENTS AND MEASUREMENTS: Prospective study with FPLD2 patients (n = 24) and controls (n = 24), who underwent anthropometric, body composition, metabolic profile and adipokines/cytokine plasma measurements. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5 and 1.0 mg of dexamethasone (DEX) given at 23:00 hours. Glucocorticoid receptor (GR) and 11ßHSD isoforms expression were assessed by qPCR. RESULTS: Familial partial lipodystrophy type 2 individuals presented increased waist and neck circumferences, decreased hip circumference, peripheral skinfold thickness and fat mass. Patients presented increased HOMA-IR, triglycerides, TNF-α, IL-1ß, IL-6 and IL-10, and decreased adiponectin and leptin plasma levels. FPLD2 patients showed decreased ability to suppress the HPA axis compared with controls after 0.5 mg DEX. The phenotype was more pronounced in patients harbouring the p.R482W LMNA mutation. GRß overexpression in PBMC was observed in female patients compared with female controls. CONCLUSIONS: Familial partial lipodystrophy type 2 patients exhibited anthropometric, clinical and biochemical phenotypic heterogeneity related to LMNA mutation sites and to gender. LMNA mutations affecting both lamin A and lamin C lead to more severe phenotype. FPLD2 patients also showed blunted HPA axis response to DEX, probably due to the association of increased levels of proinflammatory cytokines with GRß overexpression leading to a more severe phenotype in female.

Asunto(s)

Glucocorticoides/farmacología , Lipodistrofia Parcial Familiar/sangre , Lipodistrofia Parcial Familiar/metabolismo , Adiponectina/sangre , Composición Corporal/efectos de los fármacos , Composición Corporal/fisiología , Dexametasona/farmacología , Femenino , Humanos , Hidrocortisona/sangre , Resistencia a la Insulina/genética , Interleucina-10/sangre , Interleucina-1beta/sangre , Interleucina-6/sangre , Lamina Tipo A/genética , Leptina/sangre , Lipodistrofia Parcial Familiar/genética , Masculino , Mutación/genética , Estudios Prospectivos , Isoformas de Proteínas/genética , Receptores de Glucocorticoides/genética , Factor de Necrosis Tumoral alfa/sangre

Asunto(s)

Gónadas/metabolismo , Lamina Tipo A/genética , Mosaicismo , Distrofias Musculares/genética , Alelos , Estudios de Asociación Genética , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Distrofias Musculares/diagnóstico , Linaje

RESUMEN

The nucleus is physically linked to the cytoskeleton, adhesions, and extracellular matrix-all of which sustain forces, but their relationships to DNA damage are obscure. We show that nuclear rupture with cytoplasmic mislocalization of multiple DNA repair factors correlates with high nuclear curvature imposed by an external probe or by cell attachment to either aligned collagen fibers or stiff matrix. Mislocalization is greatly enhanced by lamin A depletion, requires hours for nuclear reentry, and correlates with an increase in pan-nucleoplasmic foci of the DNA damage marker γH2AX. Excess DNA damage is rescued in ruptured nuclei by cooverexpression of multiple DNA repair factors as well as by soft matrix or inhibition of actomyosin tension. Increased contractility has the opposite effect, and stiff tumors with low lamin A indeed exhibit increased nuclear curvature, more frequent nuclear rupture, and excess DNA damage. Additional stresses likely play a role, but the data suggest high curvature promotes nuclear rupture, which compromises retention of DNA repair factors and favors sustained damage.

Asunto(s)

Núcleo Celular/metabolismo , Reparación del ADN , Histonas/metabolismo , Lamina Tipo A/metabolismo , Células A549 , Núcleo Celular/genética , Histonas/genética , Humanos , Lamina Tipo A/genética

RESUMEN

Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

Asunto(s)

Síndrome de Cushing/genética , Cardiopatías/genética , Lamina Tipo A/genética , Lipodistrofia/genética , Síndrome Metabólico/genética , Miositis/genética , Femenino , Humanos , Persona de Mediana Edad , Síndrome

RESUMEN

Summary Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.

Asunto(s)

Humanos , Femenino , Persona de Mediana Edad , Síndrome de Cushing/genética , Síndrome Metabólico/genética , Lamina Tipo A/genética , Cardiopatías/genética , Lipodistrofia/genética , Miositis/genética , Síndrome

Asunto(s)

Lamina Tipo A/genética , Progeria/tratamiento farmacológico , Progeria/genética , Núcleo Celular/patología , Preescolar , Inhibidores Enzimáticos/uso terapéutico , Farnesiltransferasa/antagonistas & inhibidores , Femenino , Humanos , Lamina Tipo A/metabolismo , Mutación , Piperidinas/uso terapéutico , Progeria/diagnóstico , Progeria/patología , Piridinas/uso terapéutico

RESUMEN

INTRODUCTION: Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective lack of subcutaneous fat, which is associated with insulin-resistant diabetes. The Dunnigan variety (FPLD2) is caused by several missense mutations in the lamin A/C (LMNA) gene, most of which are typically located in exon 8 at the codon position 482. OBJECTIVE: The aim of this study was to assess and compare the dietary intake, leisure-time physical activity (LTPA), and biochemical measurements (glucose, A1C, and plasma lipids) in women with FPLD2 and without (control group, CG) and to examine the associations between dietary intake and biochemical measurements (BM). METHODS: LTPA was measured with a questionnaire and metabolic equivalent (MET) hours per week (hours/week) were calculated. Dietary intake by the 3-day recall method and clinical laboratory parameters were collected. RESULTS: Characteristics of women with FPLD2: 35.8 ± 13.9 years, fat mass = 10 ± 2.3 kg and fat free mass = 41.4 ± 4.5 kg (p < 0.05). Women with FPLD2 showed a smaller intake of energy (kcal), lipids, and carbohydrates and a large intake of protein (p < 0.01) compared to CG. Comparing the 2 groups in terms of LTPA, 78% of women with FPLD2 performed insufficient physical activity. In addition, they had a higher levels of glucose, A1C, and triglycerides (TG) and lower levels of high-density lipoprotein (HDL). There was no correlation between dietary intake and biochemical measurements. CONCLUSIONS: Women with FPLD2 have a lower intake of energy (kcal), lipids, and carbohydrates and greater changes in biochemical measurements. Because this is a rare disease, future studies are needed with encouragement of the practice of physical activity and of healthy eating habits, preventing the onset of diseases.

Asunto(s)

Ingestión de Alimentos/fisiología , Metabolismo Energético/fisiología , Ejercicio Físico , Lamina Tipo A/metabolismo , Lipodistrofia Parcial Familiar/metabolismo , Adulto , Estudios Transversales , Ingestión de Alimentos/genética , Metabolismo Energético/genética , Femenino , Humanos , Lamina Tipo A/genética , Lipodistrofia Parcial Familiar/genética , Persona de Mediana Edad , Mutación , Adulto Joven

RESUMEN

Nuclear lamins support the nuclear envelope and provide anchorage sites for chromatin. They are involved in DNA synthesis, transcription, and replication. It has previously been reported that the lack of Lamin A/C expression in lymphoma and leukaemia is due to CpG island promoter hypermethylation. Here, we provide evidence that Lamin A/C is silenced via this mechanism in a subset of neuroblastoma cells. Moreover, Lamin A/C expression can be restored with a demethylating agent. Importantly, Lamin A/C reintroduction reduced cell growth kinetics and impaired migration, invasion, and anchorage-independent cell growth. Cytoskeletal restructuring was also induced. In addition, the introduction of lamin Δ50, known as Progerin, caused senescence in these neuroblastoma cells. These cells were stiffer and developed a cytoskeletal structure that differed from that observed upon Lamin A/C introduction. Of relevance, short hairpin RNA Lamin A/C depletion in unmethylated neuroblastoma cells enhanced the aforementioned tumour properties. A cytoskeletal structure similar to that observed in methylated cells was induced. Furthermore, atomic force microscopy revealed that Lamin A/C knockdown decreased cellular stiffness in the lamellar region. Finally, the bioinformatic analysis of a set of methylation arrays of neuroblastoma primary tumours showed that a group of patients (around 3%) gives a methylation signal in some of the CpG sites located within the Lamin A/C promoter region analysed by bisulphite sequencing PCR. These findings highlight the importance of Lamin A/C epigenetic inactivation for a subset of neuroblastomas, leading to enhanced tumour properties and cytoskeletal changes. Additionally, these findings may have treatment implications because tumour cells lacking Lamin A/C exhibit more aggressive behaviour.

Asunto(s)

Neoplasias Encefálicas/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Lamina Tipo A/genética , Neuroblastoma/genética , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/ultraestructura , Secuencia de Bases , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Islas de CpG , Humanos , Lamina Tipo A/antagonistas & inhibidores , Lamina Tipo A/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neuroblastoma/metabolismo , Neuroblastoma/patología , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/metabolismo , Neuronas/patología , Cultivo Primario de Células , Regiones Promotoras Genéticas , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal

RESUMEN

Recently, studies on the pathogenesis of dilated cardiomyopathy (DCM) have focused on the underlying molecular biology and the association between single nucleotide polymorphisms (SNPs) and disease. This study was designed to explore the association between the rs4641 SNP of the LMNA gene and DCM in order to identify a new gene locus related to DCM. Polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing were employed to detect and genotype rs4641 in 198 patients with DCM and 160 healthy controls. Genotype and allele frequencies were compared to discover their relationship and logistic regression was used to assess the risk of DCM associated with the polymorphic variants. In the DCM group, the frequencies of the TC and TT genotypes and the T allele of rs4641 were remarkably higher than those in the control group (P < 0.01). According to risk analysis, taking the CC genotype as a reference, both the TC and TT genotypes increased the risk of DCM pathogenesis, with OR (95%CI) values of 5.957 (2.903- 12.222) and 6.424 (2.156-19.141), respectively. Taking the C allele as the reference, presence of the T allele was found to increase DCM risk, with OR (95%CI) of 5.295 (3.121-8.983). These results suggested that the C to T mutation at the rs4641 locus of LMNA could enhance the risk of DCM, and that rs4641 represented a genetic susceptibility locus. Therefore, it was concluded that the LMNA rs4641 SNP was associated with DCM risk, which indicated that LMNA is a susceptibility gene for DCM.

Asunto(s)

Alelos , Cardiomiopatía Dilatada/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Lamina Tipo A/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Adulto Joven

RESUMEN

Leishmaniasis development is multifactorial; nonetheless, the establishment of the infection, which occurs by the survival and replication of the parasite inside its main host cell, the macrophage, is mandatory. Thus, the importance of studying the molecular mechanisms involved in the Leishmania-macrophage interaction is highlighted. The aim of this study was to characterize a cellular model of macrophages derived from U937 cells that would allow for the identification of infection phenotypes induced by genetic silencing with interference RNA in the context of macrophages infected with Leishmania (Viannia) braziliensis. The model was standardized by silencing an exogenous gene (gfp), an endogenous gene (lmna) and a differentially expressed gene between infected and non-infected macrophages (gro-ß). The silencing process was successful for the three genes studied, obtaining reductions of 88·9% in the GFP levels, 87·5% in LMNA levels and 74·4% for Gro-ß with respect to the corresponding control cell lines. The cell model revealed changes in the infection phenotype of the macrophages in terms of number of amastigotes per infected macrophage, number of amastigotes per sampled macrophage and percentage of infected macrophages as a result of gene silencing. Thus, this cell model constitutes a research platform for the study of parasite-host interactions and for the identification of potentially therapeutic targets.

Asunto(s)

Silenciador del Gen/fisiología , Leishmania braziliensis/genética , Macrófagos/parasitología , Quimiocina CXCL2/genética , Proteínas Fluorescentes Verdes/genética , Células HEK293 , Interacciones Huésped-Parásitos/genética , Humanos , Procesamiento de Imagen Asistido por Computador , Lamina Tipo A/genética , Leishmania braziliensis/fisiología , Macrófagos/inmunología , Fenotipo , Interferencia de ARN , Células U937