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Alagille syndrome

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Alagille syndrome

  1. 1. Danny Arroyave Zuluaga Sergio Andrés Romero Seguro TERCER SEMESTRE PROFESORA: LINA MARIA MARTINEZ
  2. 2.      Is a multisystem disorder with an autosomic dominant pattern. 20–89% of the cases to mutations in the JAG1 gene. JAG1 gene is located at 20p12.2. Presents so far more than 300 mutations. ALGS has been one of the main reasons for referral for transplantation of liver.
  3. 3. organ alteration Liver particularly presenting bile duct paucity heart peripheral pulmonary artery stenosis kidneys renal dysplasia, renal tubular acidosis, among others skeletal system butterfly vertebrae characteristic facial features broad forehead, deep-set eyes, pointed chin and a triangular face eyes
  4. 4. Polymorphism  alternatives are isoforms of a gene in a population. affects both gonadal and somatic cells, so it can be transmitted following the laws of Mendelian inheritance.  Mutations  permanent change occurred in the base sequence of the DNA of an organism. are only affects inheritable when gonadal cells and not when exclusively affects somatic cells. 
  5. 5. recognize and investigate the JAG1 gene, which could help us in the clinical monitoring of these patients. 
  6. 6.  Extracción de Dna: Ruptura de las celulas (detergentes y enzimas).  Eliminacion de proteinas.  Eliminacion de ARN.  Extracción de proteinas.  Precipitaciones del ADN. 
  7. 7. DHPLC  Técnica cromatografía para la separación y el análisis de fragmentos de ADN con diferente longitud y/o composición de base  RT-PCR  Amplificación de RNA a través de la síntesis previa de su DNAc (copia), utilizando una transcriptasa inversa, seguido de varios ciclos de PCR convencional. Con esta técnica se puede determinar la expresión de genes en diversos tejidos. 
  8. 8.  Secuenciación  a) b) Tiene métodos tanto químicos como enzimáticos Químicos: marcaje del DNA, hidrólisis química selectiva del DNA y análisis de los productos Enzimático: síntesis enzimática, análisis de los fragmentos y automatización
  9. 9.    Su objetico es la amplificación directa de un gen o un fragmento de DNA o indirecta de un RNA Se basa en amplificación enzimática in vitro, que es el incremento geométrico del numero de copias de una secuencia particular del DNA Técnica metodológica
  10. 10. 1. 2. Desnaturalización: calentamiento para las separación de las dos hebras de DNA, mediantes incubación breve a una temperatura entre 90-97 grados centígrados Alineamiento: hibridación de las hebras sencillas del DNA de interés con los primers y DNTp's. A una temperatura de 37 a 65 grados centígrados
  11. 11. 3. Síntesis: amplificación en la que la DNA polimerasa elonga los primers empleando como molde ambas hebras originales. La replicación transcurre en dirección 5‘ a 3‘.
  12. 12. Fig 1. A y C NM por DHPLC ; B y D Electropherogram.
  13. 13. Fig 2. Mutación por splicing Nuevo con especificación entre La región exon1 a exon2.
  14. 14. Fig 3. Perdida de exón 4 confirmada Posterior a RT PCR.
  15. 15. AUTHOR (Onouchi et al., 1999) Heritage et al. (2002). WHAT DID HE SAY? “In the case of the intron 4–5 mutation described (and as has been previously reported for other abnormal splicing mutation affecting the following downstream base in the donor splicing site), this change could generate a less severe phenotype.” “The present study further supports the idea that the molecular mechanisms involved in the clinical effect of the mutations in ALGS is the haploinsufficiency mainly due to the loss of the transmembranal or the DSL domains (NMD). THEY ARE AGREE? YES OR NOT NO YES
  16. 16. AUTHOR (Kamath et al., 2012; Mc Daniel et al., 2006). (Mátyás et al., 2002). WHAT DID HE SAY? “Finally, in our study we observed that in 2 patients with ALGS clinical diagnosis there were no mutations identified in JAG1, however, we cannot discard the presence of mutations in other regions of the gene (such as the promoter) or in NOTCH2 gene” “It has been demonstrated that polymorphic changes detection is difficult when there are two variations in the same amplicon” THEY ARE AGREE? YES OR NOT YES YES
  17. 17. 1. 2. Is really important that we (medicine society), start a process in the early determination of mutations in the newborn. The field of the mutations moves really fast, and maybe the solution is not try to stop it, is work hard and fast as they do.
  18. 18. 3. We think that it could be a good solution, the implemetation of a law that allow the people to make a genomic exam for free. 4. The people should know more about its history, and where they are from, this would be really helpful to make a geographic location and try to know, when all these things start and where come from.

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