RESUMEN

Marfan syndrome (MFS) is an autosomal dominant condition with pleiotropic manifestations involving the skeletal, ocular, and cardiovascular systems. The diagnosis is based primarily on clinical involvement of these and other systems, referred to as the Ghent criteria. We have identified three Hispanic families from Mexico with cardiovascular and ocular manifestations due to novel FBN1 mutations but with paucity of skeletal features. The largest family, hMFS001, had a frameshift mutation in exon 24 (3075delC) identified as the cause of aortic disease in the family. Assessment of eight affected adults revealed no major skeletal manifestation of MFS. Family hMFS002 had a missense mutation (R1530C) in exon 37. Four members fulfilled the criteria for ocular and cardiovascular phenotype but lacked skeletal manifestations. Family hMFS003 had two consecutive missense FBN1 mutations (C515W and R516G) in exon 12. Eight members fulfilled the ocular criteria for MFS and two members had major cardiovascular manifestations, however none of them met criteria for skeletal system. These data suggest that individuals of Hispanic descent with FBN1 mutations may not manifest skeletal features of the MFS to the same extent as Caucasians. We recommend that echocardiogram, ocular examination and FBN1 molecular testing be considered for any patients with possible MFS even in the absence of skeletal features, including Hispanic patients.

Asunto(s)

Síndrome de Marfan/genética , Proteínas de Microfilamentos/genética , Mutación Missense , Adulto , Enfermedades Cardiovasculares/genética , Análisis Mutacional de ADN , Exones , Salud de la Familia , Femenino , Fibrilina-1 , Fibrilinas , Humanos , Masculino , Síndrome de Marfan/etnología , México , Modelos Genéticos , Mutación , Linaje , Fenotipo

RESUMEN

OBJECTIVE: Lipoic acid synthase (LASY) is the enzyme that is involved in the endogenous synthesis of lipoic acid, a potent mitochondrial antioxidant. The aim of this study was to study the role of LASY in type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied expression of LASY in animal models of type 2 diabetes. We also looked at regulation of LASY in vitro under conditions that exist in diabetes. Additionally, we looked at effects of LASY knockdown on cellular antioxidant status, inflammation, mitochondrial function, and insulin-stimulated glucose uptake. RESULTS: LASY expression is significantly reduced in tissues from animal models of diabetes and obesity compared with age- and sex-matched controls. In vitro, LASY mRNA levels were decreased by the proinflammatory cytokine tumor necrosis factor (TNF)-alpha and high glucose. Downregulation of the LASY gene by RNA interference (RNAi) reduced endogenous levels of lipoic acid, and the activities of critical components of the antioxidant defense network, increasing oxidative stress. Treatment with exogenous lipoic acid compensated for some of these defects. RNAi-mediated downregulation of LASY induced a significant loss of mitochondrial membrane potential and decreased insulin-stimulated glucose uptake in skeletal muscle cells. In endothelial cells, downregulation of LASY aggravated the inflammatory response that manifested as an increase in both basal and TNF-alpha-induced expression of the proinflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1). Overexpression of the LASY gene ameliorated the inflammatory response. CONCLUSIONS: Deficiency of LASY results in an overall disturbance in the antioxidant defense network, leading to increased inflammation, insulin resistance, and mitochondrial dysfunction.

Asunto(s)

Diabetes Mellitus Tipo 2/enzimología , Inflamación/fisiopatología , Resistencia a la Insulina , Mitocondrias/enzimología , Sulfurtransferasas/genética , Animales , Aorta , Modelos Animales de Enfermedad , Regulación hacia Abajo , Endotelio Vascular/enzimología , Eliminación de Gen , Humanos , Inflamación/enzimología , Ratones , Músculo Esquelético/enzimología , Mioblastos/enzimología , Obesidad/enzimología , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , Ratas , Sulfurtransferasas/deficiencia , Sulfurtransferasas/metabolismo , Transfección

RESUMEN

Members of the lipase family that include lipoprotein lipase, hepatic lipase and endothelial cell lipase play a central role in triglyceride and phospholipid hydrolysis. Because the site of action of these lipases is the endothelium, the endothelium is constantly exposed to products of lipolysis. These lipolysis products could elicit pro- or anti-inflammatory effects in endothelial as well as surrounding cells. These effects could be transient or long-term depending on the nutritional state. While lipolysis is per se anti-atherogenic due to its triglyceride lowering activity, it could also be pro-atherogenic due to prolonged exposure of endothelium to lipolysis products. In addition, lipoprotein lipase expressed in macrophages appears to be pro-atherogenic independent of plasma lipoproteins. In this review we summarize these pro- and anti-inflammatory consequences of lipolysis with respect to atherosclerosis.

Asunto(s)

Aterosclerosis/enzimología , Vasos Sanguíneos/enzimología , Inflamación/enzimología , Lipasa/metabolismo , Endotelio Vascular/enzimología , Humanos , Lipólisis , Hígado/enzimología , Macrófagos/enzimología

RESUMEN

BACKGROUND: A genetic predisposition for progressive enlargement of thoracic aortic aneurysms leading to type A dissection (TAAD) is inherited in an autosomal-dominant manner in up to 19% of patients, and a number of chromosomal loci have been identified for the condition. Having mapped a TAAD locus to 3p24-25, we sequenced the gene for transforming growth factor-beta receptor type II (TGFBR2) to determine whether mutations in this gene resulted in familial TAAD. METHODS AND RESULTS: We sequenced all 8 coding exons of TGFBR2 by using genomic DNA from 80 unrelated familial TAAD cases. We found TGFBR2 mutations in 4 unrelated families with familial TAAD who did not have Marfan syndrome. Affected family members also had descending aortic disease and aneurysms of other arteries. Strikingly, all 4 mutations affected an arginine residue at position 460 in the intracellular domain, suggesting a mutation "hot spot" for familial TAAD. Despite identical mutations in the families, assessment of linked polymorphisms suggested that these families were not distantly related. Structural analysis of the TGFBR2 serine/threonine kinase domain revealed that R460 is strategically located within a highly conserved region of this domain and that the amino acid substitutions resulting from these mutations will interfere with the receptor's ability to transduce signals. CONCLUSIONS: Germline TGFBR2 mutations are responsible for the inherited predisposition to familial TAAD in 5% of these cases. Our results have broad implications for understanding the role of TGF-beta signaling in the pathophysiology of TAAD.

Asunto(s)

Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Mutación , Receptores de Factores de Crecimiento Transformadores beta/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/química , Transducción de Señal

RESUMEN

The major diseases affecting the aorta are aortic aneurysms and dissections, with patients with acute dissections often presenting in the emergency department (ED). Recent studies demonstrate a strong genetic predisposition to thoracic aortic aneurysms and dissections, independent of syndromes traditionally considered to predispose to aortic disease (such as Marfan syndrome). Nonsyndromic familial thoracic aortic aneurysms and dissections are inherited in families as an autosomal dominant disorder and a variable age of onset of the aortic disease. The case reported here illustrates the critical importance of obtaining a family history of thoracic aortic aneurysms and dissections, along with unexplained sudden death, when assessing an individual with chest pain in the ED, regardless of age and in the absence of a known genetic syndrome.

Asunto(s)

Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/genética , Disección Aórtica/diagnóstico , Disección Aórtica/genética , Servicio de Urgencia en Hospital , Familia , Predisposición Genética a la Enfermedad , Adulto , Anciano , Disección Aórtica/epidemiología , Aneurisma de la Aorta Torácica/epidemiología , Dolor en el Pecho/diagnóstico , Dolor en el Pecho/epidemiología , Mapeo Cromosómico , Diagnóstico Diferencial , Medicina de Emergencia/métodos , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Anamnesis , Linaje

RESUMEN

BACKGROUND: Familial thoracic aortic aneurysms and dissections (TAAD) occur as part of known syndromes such as Marfan syndrome but can also be inherited in families in an autosomal dominant manner as an isolated condition. Previous studies have mapped genes causing nonsyndromic familial TAAD to 5q13-15 (TAAD1) and 11q23.2-q24 (FAA1). Further genetic heterogeneity for the condition was evident by the presence of TAAD in some families not linked to these known loci. METHODS AND RESULTS: A 4-generation family with dominant mode of inheritance of TAAD was studied. Affected status was determined by dilation of the ascending aorta, surgical repair of an aneurysm or dissection, or death as the result of aortic dissection. None of the family members evaluated met the diagnostic criteria for Marfan syndrome. After exclusion of known loci for familial TAAD, a genome-wide scan was carried out to map the defective gene causing the disease in the family. A locus was mapped to a 25-cM region on 3p24-25 with a maximum multipoint logarithm of the odds score of 4.28. CONCLUSIONS: A third locus for nonsyndromic TAAD was mapped to 3p24-25 and termed the TAAD2 locus. This locus overlaps a previously mapped second locus for Marfan syndrome, termed the MFS2 locus. Future characterization of the TAAD2 gene will determine if TAAD2 is allelic to MFS2. In addition, identification of the TAAD2 gene will improve the presymptomatic diagnosis of individuals with this life-threatening genetic syndrome and provide information concerning the pathogenesis of the disease.

Asunto(s)

Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Mapeo Cromosómico , Cromosomas Humanos Par 3/genética , Adolescente , Adulto , Disección Aórtica/diagnóstico , Disección Aórtica/epidemiología , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/epidemiología , Proteínas de Unión al Calcio/genética , Niño , Comorbilidad , Análisis Mutacional de ADN , Ecocardiografía , Proteínas de la Matriz Extracelular/genética , Femenino , Genes Dominantes , Ligamiento Genético , Marcadores Genéticos , Genotipo , Alemania/epidemiología , Haplotipos , Humanos , Escala de Lod , Masculino , Síndrome de Marfan/epidemiología , Síndrome de Marfan/genética , Persona de Mediana Edad , Linaje , Penetrancia , Suiza/epidemiología

RESUMEN

The major diseases affecting the aorta are aortic aneurysms and dissections, which are classified based on anatomic location. Diseases affecting the ascending aorta, such as thoracic aortic aneurysms and type I and II dissections, are primarily associated with medial necrosis on pathologic examination. Medial necrosis is characterized by fragmentation and loss of elastic fibers, loss of smooth muscle cells, and interstitial collections of collagenous tissue and basophilic ground substance. Medial necrosis occurs as part of the normal aging of the aorta but is accelerated by other conditions, including hypertension and genetic alterations that predispose persons to these aortic diseases. The etiologies of many of the genetic syndromes, such as Marfan syndrome, that predispose persons to thoracic aortic aneurysms and dissections are understood. Studies are just beginning to elucidate the genes that predispose persons without known syndromes to these aortic diseases, and a major locus for this condition, termed the TAAD1 locus, has been mapped to 5q13-14. Future characterization of this gene and others will enhance the ability to determine persons at risk for aortic aneurysms and dissections and will define molecular mechanisms involved in the pathogenesis of this disorder.

Asunto(s)

Aneurisma de la Aorta Torácica/genética , Disección Aórtica/genética , Disección Aórtica/epidemiología , Aneurisma de la Aorta Torácica/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Síndrome de Marfan/epidemiología , Síndrome de Marfan/genética , Factores de Riesgo