RESUMEN
The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance.
Asunto(s)
Proteínas de Microfilamentos/genética , Mutación/genética , Esclerodermia Sistémica/congénito , Esclerodermia Sistémica/genética , Piel/patología , Biopsia , Adhesión Celular , Movimiento Celular , Colágeno/metabolismo , Análisis Mutacional de ADN , Elastina/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Familia , Femenino , Fibrilina-1 , Fibrilinas , Humanos , Inmunohistoquímica , Masculino , Mesodermo/patología , Microfibrillas/metabolismo , Microfibrillas/patología , Proteínas de Microfilamentos/metabolismo , Linaje , Fenotipo , Esclerodermia Sistémica/patología , Transducción de Señal , Piel/ultraestructura , Síndrome , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Aortic complications account for the major mortality in Marfan syndrome (MFS), a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1. We hypothesized that MFS impaired endothelial function and nitric oxide (NO) production in the aorta. EXPERIMENTAL APPROACH: Mice (at 3, 6, 9 and 12 months of age) heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1 (C1039G/+), Marfan mice, n=75), the most common class of mutation in MFS, were compared with age-matched control littermates (n=75). Thoracic and abdominal aortas from the two groups were studied. KEY RESULTS: Isometric force measurements revealed that relaxation to ACh (but not to sodium nitroprusside) was diminished in the phenylephrine-precontracted Marfan thoracic aorta at 6 months of age (pEC(50)=6.12+/-0.22; maximal response, E(max)=52.7+/-6.8%; control: pEC(50)=7.34+/-0.19; E(max)=84.8+/-2.2%). At one year, both inhibition of NO production with N(omega)-nitro-L-arginine methyl ester, or denudation of endothelium increased the phenylephrine-stimulated contraction in the control thoracic aorta by 35%, but had no effect in the Marfan aorta, indicating a loss of basal NO production in the Marfan vessel. From 6 months, a reduced phosphorylation of endothelial NOS (eNOS)(Ser1177) and Akt(Thr308) detected by Western blotting was observed in the Marfan thoracic aorta, which was accompanied by decreased levels of cGMP. Expressions of Akt and eNOS in the abdominal aorta were not different between the two groups. CONCLUSIONS AND IMPLICATIONS: MFS impairs endothelial function and signaling of NO production in the thoracic aorta, suggesting the importance of NO in the age-related progression of thoracic aortic manifestations.
Asunto(s)
Aorta Torácica/metabolismo , Endotelio Vascular/metabolismo , Síndrome de Marfan/metabolismo , Proteínas de Microfilamentos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Vasodilatación , Acetilcolina/farmacología , Factores de Edad , Animales , Aorta Abdominal/metabolismo , Aorta Abdominal/fisiopatología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiopatología , Calcio/metabolismo , GMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Inhibidores Enzimáticos/farmacología , Fibrilina-1 , Fibrilinas , Síndrome de Marfan/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos/genética , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Fosforilación , Transducción de Señal/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix-cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin-rich microfibrils. Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained.
Asunto(s)
Síndrome de Marfan/genética , Receptores de Activinas Tipo I/genética , Disección Aórtica/genética , Animales , Aneurisma de la Aorta Torácica/genética , Proteínas Contráctiles/fisiología , Bases de Datos Genéticas , Proteínas de la Matriz Extracelular/fisiología , Fibrilina-1 , Fibrilinas , Humanos , Proteínas de Unión a TGF-beta Latente/genética , Síndrome de Marfan/complicaciones , Ratones , Microfibrillas/metabolismo , Proteínas de Microfilamentos/genética , Modelos Animales , Modelos Biológicos , Desnaturalización Proteica/genética , Proteínas Serina-Treonina Quinasas , Factores de Empalme de ARN , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genéticaRESUMEN
An association between dilated cardiomyopathy and glucagonoma has not previously been described. A case of a 54 year old woman with tachycardia and congestive heart failure is described. Initial evaluation included an echocardiogram, which showed dilated cardiomyopathy with an ejection fraction of 15%. Coronary angiography and endomyocardial biopsy did not identify a secondary cause of her cardiomyopathy. She subsequently developed necrolytic migratory erythema, and imaging of her pancreas identified a pancreatic mass with a major increase of her serum glucagon concentration. Tachycardia persisted despite treatment with beta blockers. After resection of her tumour, her heart rate normalised and subsequently her heart returned to normal size and function. Glucagon is used to treat overdoses of beta blockers and calcium channel blockers, increasing heart rate by increasing myocardial cyclic AMP concentrations. Although rare, in the appropriate clinical setting, glucagonoma should be considered in the differential diagnosis for tachycardia and dilated cardiomyopathy.
Asunto(s)
Cardiomiopatía Dilatada/etiología , Glucagonoma/complicaciones , Neoplasias Pancreáticas/complicaciones , Cardiomiopatía Dilatada/diagnóstico por imagen , Femenino , Glucagonoma/cirugía , Humanos , Metástasis Linfática , Persona de Mediana Edad , Neoplasias Pancreáticas/cirugía , Taquicardia Sinusal/etiología , UltrasonografíaRESUMEN
Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue with marked interfamilial and intrafamilial variation in phenotype. The primary defect in affected patients resides in the gene for fibrillin-1 (FBN1) on 15q21. Linkage analysis has shown no locus heterogeneity in the classic phenotype, although substantial allelic heterogeneity exists. Recently it has been shown that the size of the gene is approximately 200 kb. These and other factors have precluded routine mutation screening for presymptomatic and prenatal diagnosis. Previously we described four intragenic microsatellite polymorphisms that can be used for haplotype segregation analysis. The utility of this approach is limited because the markers do not fully span the gene and show incomplete informativeness, with 16% homozygosity for the most common haplotype. We have now identified and localized highly polymorphic microsatellite markers that fall within 1 Mb of FBN1. Complete haplotype heterozygosity was observed in a population of 50 unrelated control individuals when the flanking markers and existing intragenic polymorphisms were used in combination. We demonstrate the utility of haplotype segregation analysis in the presymptomatic diagnosis and counseling of families showing atypical or equivocal manifestations of MFS.