Relaciones genotipo-fenotipo en Hemofilia. Desarrollo de un esquema de análisis molecular para mejorar la atención médica de las familias con Hemofilia
Haemophilia is a key disease to study human genetics.\nThe objectives of the work are to improve the molecular diagnostic tools and contribute to the\nknowledge of the genotype-phenotype relationship in Haemophilia A (HA).\nTo improve the determination of the causal defect, a scheme including F8-ana...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica
2019
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_6379 https://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_6379.dir/6379.PDF |
| Aporte de: |
| Sumario: | Haemophilia is a key disease to study human genetics.\nThe objectives of the work are to improve the molecular diagnostic tools and contribute to the\nknowledge of the genotype-phenotype relationship in Haemophilia A (HA).\nTo improve the determination of the causal defect, a scheme including F8-analysis and\npathogenicity assignment was developed and adjusted, allowing characterization 96% of the\nfamilies with HA (n=911 individuals).\nA family with HA and a deletion of the F8-promoter (Del2kb) was reported: a severe proband, a\ncarrier mother, a non-carrier aunt, and a mild grandfather (FVIII:C=35%) showing a combined\nsomatic/germinal mosaicism. An allele-specific qPCR approach for Del2KB, on bloodmesoderm/\nsaliva-ectoderm/urine-endoderm, allowed inferring the production of FVIII in\nhepatocytes-endoderm (Normal%?34%) and gonads-epiblast (Del2kb%?60%) in the mosaic in\nclose coincidence with his phenotype.\nCase-control studies in HA-severe patients (n=404) allowed determination of absolute inhibitor\nrisks differing from the average (18%) associated with some F8-genotypes: multi-exonic\ndeletions (86.9%, P=0.0006), -intron 22 inversion (24.7%, P=0.0011) and -missense (1.2%,\nP<0.0001). Studies in affected siblings showed additional inhibitor-predisposing factors. Studies\non immunoregulatory genes indicated high inhibitor risks for the variant CTLA4:p.Thr17Ala\n(OR=2.11, P=0.0025).\nThese findings contribute to improve and extend the medical care of the patient with HA and\nhis family. |
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