Hemofilia: diagnóstico molecular y alternativas de tratamiento
TL;DR: In this paper, otras terapias alternas, aunque estan en fase de investigación, permitirian obtener una produccion de proteina a largo termino and que se han desarrollado gracias al entendimiento de la naturaleza molecular de los factores de la coagulacion.
Abstract: La hemofilia es una enfermedad recesiva ligada al cromosoma X que generalmente padecen los hombres. El diagnostico genetico preimplantacion (DGP), el diagnostico prenatal y el diagnostico molecular de las mutaciones que causan hemofilia, se realizan en investigaciones aisladas con el fin de hacer prevencion primaria, asesorar a las portadoras y a sus familias, lo que ha permitido traer al mundo ninos libres de esta enfermedad y tambien mejorar la calidad de vida de los afectados. Los esperanzadores procedimientos en terapia genica (TG) han mostrado gran efectividad, se pretende con ella la produccion normal de la proteina que esta ausente o alterada en los afectados, pero en el momento los ensayos que se llevan a cabo en seres humanos estan detenidos. Aqui se muestran otras terapias alternas que aunque estan en fase de investigacion, permitirian obtener una produccion de proteina a largo termino y que se han desarrollado gracias al entendimiento de la naturaleza molecular de los factores de la coagulacion.
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TL;DR: The results establish a general overview of population exposure and can be a scientific tool to improve environmental health policies in the country and could strengthen Colombia’s efforts to increase the practice of breastfeeding.
4 citations
TL;DR: In this paper , the authors applied species richness estimation methods from ecology to estimate "variant richness" and determine how many germline pathogenic BRCA1/2 variants have yet to be identified and the frequency of these missing variants in different populations.
Abstract: There have been many surveys of genetic variation in BRCA1 and BRCA2to identify variant prevalence and catalogue population specific variants, yet none have evaluated the magnitude of unobserved variation. We applied species richness estimation methods from ecology to estimate "variant richness" and determine how many germline pathogenic BRCA1/2 variants have yet to be identified and the frequency of these missing variants in different populations. We also estimated the prevalence of germline pathogenic BRCA1/2 variants and identified those expected to be most common. Data was obtained from a literature search including studies conducted globally that tested the entirety of BRCA1/2 for pathogenic variation. Across countries, 45% to 88% of variants were estimated to be missing, i.e., present in the population but not observed in study data. Estimated variant frequencies in each country showed a higher proportion of rare variants compared to recurrent variants. The median prevalence estimate of BRCA1/2 pathogenic variant carriers was 0.64%. BRCA1 c.68_69del is likely the most recurrent BRCA1/2 variant globally due to its estimated prevalence in India. Modeling variant richness using ecology methods may assist in evaluating clinical targeted assays by providing a picture of what is observed with estimates of what is still unknown.
2 citations
Journal Article•
TL;DR: A Colombian family that apparently suffered the two diseases according to clinical diagnosis and the lack of a genetic study to verify and contrast the diagnosis made by health institutions can lead to a wrong classification of von Willebrand disease as a type of mild Hemophilia.
Abstract: El Factor von Willebrand circula en el plasma formando un complejo con el Factor VIII de coagulacion por enlaces no covalentes. Esta interaccion evita la degradacion enzimatica del Factor VIII y asegura su transporte al lugar de formacion del coagulo de fibrina. Debido a su estrecha relacion, la disminucion de la actividad de un factor puede afectar la actividad del otro, lo que genera un diagnostico clinico equivocado en cuanto a que enfermedad se padece, si Hemofilia A o Enfermedad de von Willebrand. Este estudio reporta el caso de una familia colombiana que segun diagnostico clinico de su fenotipo, padecia las dos enfermedades. Sin embargo, dicha familia carecia de un estudio genetico que permitiera verificar y contrastar el diagnostico que hacen las entidades de salud. Por tal razon, se realizo un diagnostico genetico por pruebas moleculares que detectan mutaciones, como las inversiones en los intrones 1 y 22 por PCR de fragmentos largos y la secuenciacion del gen del Factor VIII, esta ultima no aplicada y publicada en Colombia hasta el momento. Se encontraron dos mutaciones sinonimas en los exones 14 y 26 que no alteran la secuencia de aminoacidos en la proteina; por tanto, se descarta la presencia de Hemofilia A en la familia. Se plantea la posibilidad de un caso de Enfermedad de von Willebrand unicamente. El estudio demuestra la necesidad que hay en el pais de ampliar las pruebas clinicas y de incluir el diagnostico genetico en casos de ambiguedad en el diagnostico de estas coagulopatias. Palabras clave: Hemofilia A, Factor VIII, Enfermedad de von Willebrand. MOLECULAR ANALYSIS OF HEMOPHILIA A IN A COLOMBIAN FAMILY WITH DIAGNOSIS OF HEMOPHILIA A AND VON WILLEBRAND DISEASE ABSTRACT Von Willebrand Factor circulates in plasma in a protein complex together with coagulation Factor VIII, joined by noncovalent bonds. This interaction prevents enzymatic degradation of Factor VIII and ensures its transport to the place of the fibrin clot formation. Because of their close relationship, decrease activity of one factor may affect the other one. The late generates a clinical diagnosis not very accurate for Hemophilia A or von Willebrand disease. We report here a Colombian family that apparently suffered the two diseases according to clinical diagnosis. However, the lack of a genetic study to verify and contrast the diagnosis made by health institutions, which is based on phenotype, only, can lead to a wrong classification of von Willebrand disease as a type of mild Hemophilia. The aim of this study was to confirm the clinical diagnosis in this family by molecular analysis. To achieve this, we identify the presence of Factor VIII gene inversions in introns 22 and 1 by LD - PCR and a general scan of the gene for frame shift mutations or stop codons through three family generations. Two synonymous mutations were found in exons 14 and 26, so no changes were observed in the aminoacid sequences, fact that disregards the presence of Hemophilia A. This family could be a case of von Willebrand disease only. The use of molecular techniques to confirm the clinical diagnosis for bleeding disorders will improve adequate treatment and patient prognosis in Colombia. Key words: Hemophilia A, Factor VIII, von Willebrand disease.
2 citations
Cites background from "Hemofilia: diagnóstico molecular y ..."
...Frecuencia de los alelos de referencia y alterno en poblaciones reportadas en NCBI para la variación rs1800292....
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...Frecuencia de los alelos de referencia y alterno en poblaciones reportadas en NCBI para la variación rs1050705....
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...Con ayuda del programa CLC Main Workbench 7 se alinearon las secuencias de cada individuo con la secuencia consenso proporcionada por NCBI (24)....
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...De acuerdo con los resultados arrojados por SIFT y PROVEAN, así como en el reporte de NCBI la variación no afecta la proteína, pues es de tipo sinónima y en consecuencia se mantiene el aminoácido serina (NP_000123....
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...Los alineamientos realizados con el programa CLC Main workbench 7 demostraron la presencia de solo dos variaciones en algunos miembros de la familia, rs1800292 y rs1050705, ya reportadas en bases de datos como NCBI, Kaviar y HAMSTeRS....
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TL;DR: In this paper , a cohort of 165 South African women of self-identified African ancestry diagnosed with breast cancer, who were unselected for family history of cancer, were analyzed using the Illumina TruSight cancer panel for targeted sequencing of 94 cancer susceptibility genes.
Abstract: Abstract Since the discovery of the breast cancer susceptibility genes, BRCA1 and BRCA2, various other genes conferring an increased risk for breast cancer have been identified. Studies to evaluate sequence variants in cancer predisposition genes among women of African ancestry are limited and mostly focused on BRCA1 and BRCA2 . To characterize germline sequence variants in cancer susceptibility genes, we analysed a cohort of 165 South African women of self-identified African ancestry diagnosed with breast cancer, who were unselected for family history of cancer. With the exception of four cases, all others were previously investigated for BRCA1 and BRCA2 deleterious variants, and were negative for pathogenic variants. We utilized the Illumina TruSight cancer panel for targeted sequencing of 94 cancer susceptibility genes. A total of 3.6% of patients carried a pathogenic/likely pathogenic variant in a known breast cancer susceptibility gene: 1.2% in BRCA1 , 0.6% in each of BRCA2 , ATM, CHEK2 and PALB, none of whom had any family history of breast cancer. The mean age of patients who carried deleterious variant in BRCA1/BRCA2 was 39 years and 8 months compared to 47 years and 3 months among women who carried a deleterious variant in other breast cancer susceptibility genes.
1 citations
29 Sep 2020
TL;DR: Hemophilia B or Christmas disease was first differentiated from hemophilia A in 1947 and is linked to the X chromosome; women are carriers, but it manifests clinically in men, although cases of symptomatic women carriers have been described.
Abstract: La hemofilia B o enfermedad de Christmas se diferencio por primera vez de la hemofilia A en 1947. Su forma clasica consiste en un trastorno hereditario de la coagulacion causado por mutaciones en el gen F9, que codifica para el factor IX de la coagulacion. Su herencia esta ligada al cromosoma X; las mujeres son portadoras, pero se manifiesta clinicamente en hombres, aunque se han descrito casos de mujeres portadoras sintomaticas. El factor IX activado es una proteina dependiente de vitamina K, sintetizada en el higado, que forma parte del complejo tenasa, cuya funcion es formar la mayor cantidad de trombina en el nuevo modelo de la coagulacion basado en celulas. De acuerdo a la actividad del factor IX, su deficiencia se puede clasificar en leve (5% a 40%), moderada (1% a 5%), o severa (<1%). Su diagnostico se realiza con la presencia de un TPT alargado que corrige con plasma normal y con la determinacion del nivel funcional del factor IX, y se confirma con el estudio molecular que demuestra la mutacion en el gen F9. Su diagnostico diferencial incluye otras patologias como la hemofilia A. El tratamiento con factor IX recombinante es el mas utilizado en la actualidad, pero se vienen desarrollando nuevas terapias con virus adeno-asociados recombinantes que prometen mejorar la calidad de vida para algunos pacientes afectados. La profilaxis juega un papel fundamental, en particular en los casos de enfermedad moderada y severa
1 citations
References
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TL;DR: The mobility shift analysis of single-stranded DNAs on neutral polyacrylamide gel electrophoresis to detect DNA polymorphisms was developed and SSCPs were found to be allelic variants of true Mendelian traits, and therefore they should be useful genetic markers.
Abstract: We developed mobility shift analysis of single-stranded DNAs on neutral polyacrylamide gel electrophoresis to detect DNA polymorphisms. This method follows digestion of genomic DNA with restriction endonucleases, denaturation in alkaline solution, and electrophoresis on a neutral polyacrylamide gel. After transfer to a nylon membrane, the mobility shift due to a nucleotide substitution of a single-stranded DNA fragment could be detected by hybridization with a nick-translated DNA fragment or more clearly with RNA copies synthesized on each strand of the DNA fragment as probes. As the mobility shift caused by nucleotide substitutions might be due to a conformational change of single-stranded DNAs, we designate the features of single-stranded DNAs as single-strand conformation polymorphisms (SSCPs). Like restriction fragment length polymorphisms (RFLPs), SSCPs were found to be allelic variants of true Mendelian traits, and therefore they should be useful genetic markers. Moreover, SSCP analysis has the advantage over RFLP analysis that it can detect DNA polymorphisms and point mutations at a variety of positions in DNA fragments. Since DNA polymorphisms have been estimated to occur every few hundred nucleotides in the human genome, SSCPs may provide many genetic markers.
3,887 citations
TL;DR: The complete 186,000 base-pair (bp) human factor VIII gene has been isolated and consists of 26 exons ranging in size from 69 to 3,106 bp and introns as large as 32.4 kilobases as mentioned in this paper.
Abstract: The complete 186,000 base-pair (bp) human factor VIII gene has been isolated and consists of 26 exons ranging in size from 69 to 3,106 bp and introns as large as 32.4 kilobases (kb). Nine kb of mRNA and protein-coding DNA has been sequenced and the mRNA termini have been mapped. The relationship between internal duplications in factor VIII and evolution of the gene is discussed.
988 citations
TL;DR: Of the various types of hemophilia, the most common of these lifelong bleeding disorders are due to an inherited deficiency of factor VIII or factor IX (Table 1).
Abstract: Of the various types of hemophilia, the most common of these lifelong bleeding disorders are due to an inherited deficiency of factor VIII or factor IX (Table 1). The genes for these blood coagulat...
964 citations
TL;DR: In the past, men with haemophilia were likely to die in their youth, but with advances in diagnosis, and especially with development of safe and effective treatment, affected individuals can now look forward to a normal life expectancy.
625 citations
TL;DR: The presence of factor VII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors than patients without inversions.
316 citations