Identificación de nuevos polimorfismos del Síndrome de Marfan, un estudio de caso
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Fecha
2020
Autores
Rondón Payares, Karin Patricia
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Ediciones Universidad Simón Bolívar
Facultad de Ciencias Básicas y Biomédicas
Facultad de Ciencias Básicas y Biomédicas
Resumen
Antecedentes: El síndrome de Marfan (SMF) es un trastorno autosómico
dominante, causado por mutaciones del gen que codifica la fibrilina‐1, es un
componente de glucoproteína de las fibras elásticas que tiene importantes
funciones estructurales y reguladoras en la matriz extracelular, lo que lleva a una
desregulación de la señalización del factor de crecimiento ‐ beta transformante
(TGF‐β), que afecta los sistemas esquelético, ocular y cardiovascular, del tejido
conectivo. Estos pacientes afectados llevan una esperanza de vida reducida, en
gran medida dependiente de complicaciones cardiovasculares. Su buen pronóstico
dependerá de un eficiente diagnóstico, tratamiento y el conocimiento del paciente
de su enfermedad.
Objetivos: Identificar los polimorfismos que influyen en la expresión del
fenotipo y calidad de vida de un individuo con Síndrome de Marfan.
Materiales y Métodos: Para ello tomamos el resultado del estudio
molecular realizado por el paciente, mediante el método de secuenciación Sanger,
el cual fue procesado y sus características de rendimiento fueron determinadas por
el Laboratorio de Diagnóstico Cardiovascular Jhon Welsh (Baylor College of
Medicine (BCM) Houston, Texas). Este laboratorio está certificado bajo las
enmiendas de mejora del laboratorio clínico de 1988 (CLIA-88), que permitió
conseguir las secuencias del resultado del estudio. A los resultados de la
secuenciación se les realizó un análisis bioinformático para relacionar los
polimorfismos encontrados en el paciente con el Síndrome de Marfan, por medio de
herramientas como: El modelamiento por homología que consiste en alinear la
secuencia de aminoácidos de la proteína con secuencias de proteínas de las cuales
ya se conoce su estructura, partiendo de observaciones donde proteínas con
funciones similares tienen estructuras similares (proteínas homologas), se usan
estas proteínas de las cuales ya se conoce su estructura para plegar la proteína
problema, las proteínas usadas como plantillas son obtenidas de la base de datos
públicas como PDB. En algunos casos la proteína problema presenta mutaciones
que son de nuestro interés y precisan ser estudiadas y analizadas, para ello se
realizaron pasos adicionales en el modelamiento de la proteína para añadirle estas
mutaciones y así verificar como estas afecta a la proteína en sí. Estas mutaciones
previamente identificadas con técnicas como secuenciación y alineamiento fueron
luego reproducidas en nuestra estructura tridimensional.
Background: Marfan syndrome (MFS) is an autosomal dominant disorder, caused by mutations in the gene encoding fibrillin-1, it is a glycoprotein component of elastic fibers that has important structural and regulatory functions in the extracellular matrix, which leads to dysregulation of transforming growth factor-beta (TGF-β) signaling, which affects the skeletal, ocular, and cardiovascular systems of connective tissue. These affected patients have a shortened life expectancy, largely dependent on cardiovascular complications. Its good prognosis will depend on an efficient diagnosis, treatment and the knowledge of the patient of his disease. Objectives: To identify the polymorphisms that influence the expression of the phenotype and quality of life of an individual with Marfan Syndrome. Materials and Methods: For this we take the result of the molecular study carried out by the patient, using the Sanger sequencing method, which was processed and its performance characteristics were determined by the Jhon Welsh Cardiovascular Diagnostic Laboratory (Baylor College of Medicine (BCM) Houston Texas). This laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), which allowed the sequences of the study result to be achieved. The results of the sequencing were subjected to a bioinformatic analysis to relate the polymorphisms found in the patient with Marfan Syndrome, using tools such as: Homology modeling, which consists of aligning the amino acid sequence of the protein with sequences of proteins whose structure is already known, based on observations where proteins with similar functions have similar structures (homologous proteins), these proteins are used whose structure is already known to fold the problem protein, the proteins used as templates are Obtained from the public database as PDB. In some cases, the problem protein presents mutations that are of our interest and need to be studied and analyzed, for this, additional steps were carried out in the modeling of the protein to add these mutations and thus verify how they affect the protein itself. These mutations previously identified with techniques such as sequencing and alignment were then reproduced in our three-dimensional structure.
Background: Marfan syndrome (MFS) is an autosomal dominant disorder, caused by mutations in the gene encoding fibrillin-1, it is a glycoprotein component of elastic fibers that has important structural and regulatory functions in the extracellular matrix, which leads to dysregulation of transforming growth factor-beta (TGF-β) signaling, which affects the skeletal, ocular, and cardiovascular systems of connective tissue. These affected patients have a shortened life expectancy, largely dependent on cardiovascular complications. Its good prognosis will depend on an efficient diagnosis, treatment and the knowledge of the patient of his disease. Objectives: To identify the polymorphisms that influence the expression of the phenotype and quality of life of an individual with Marfan Syndrome. Materials and Methods: For this we take the result of the molecular study carried out by the patient, using the Sanger sequencing method, which was processed and its performance characteristics were determined by the Jhon Welsh Cardiovascular Diagnostic Laboratory (Baylor College of Medicine (BCM) Houston Texas). This laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), which allowed the sequences of the study result to be achieved. The results of the sequencing were subjected to a bioinformatic analysis to relate the polymorphisms found in the patient with Marfan Syndrome, using tools such as: Homology modeling, which consists of aligning the amino acid sequence of the protein with sequences of proteins whose structure is already known, based on observations where proteins with similar functions have similar structures (homologous proteins), these proteins are used whose structure is already known to fold the problem protein, the proteins used as templates are Obtained from the public database as PDB. In some cases, the problem protein presents mutations that are of our interest and need to be studied and analyzed, for this, additional steps were carried out in the modeling of the protein to add these mutations and thus verify how they affect the protein itself. These mutations previously identified with techniques such as sequencing and alignment were then reproduced in our three-dimensional structure.
Descripción
Palabras clave
Codón de parada, Fibrilina, Nosología de Ghent, Síndrome de Marfan, Análisis bioinformático, Stop codon, Fibrillin, Ghent nosology, Marfan syndrome, Bioinformatic analysis