Víctor Raggio

Molecular characterization of genes modifying the age at onset in Huntington's disease in Uruguayan patients

Huntingtons disease (HD) is a hereditary neurodegenerative disorder. The genetic cause is an expansion of CAG repeats located in the IT15 gene. Though the number of CAG repeats ((CAG)n) can largely explain the age at onset (AAO) of symptoms, a percentage of its variation could be attributed to modifier genes and to environmental factors. The study aimed to evaluate the influence of genetic modifiers of the AAO of HD including: (CAG)n and del2642 in the IT15 gene, ADORA2A rs5751876, HAP1 rs4523977, PGC1-α rs7665116 and UCH-L1 rs5030732. Eighteen patients with positive family history and HD-suggestive symptoms were recruited. The (CAG)n and gene polymorphisms were determined by different molecular biology techniques. We observed that the (CAG)n influenced in a 64.5% of the variability in the AAO. We also showed that the rs5751876 variant significantly affected this variability. However, the influence of UCH-L1, del2642, HAP1 and PGC1-α gene polymorphisms could not be replicated, perhaps due to small sample size. Genetic studies including the molecular determination of (CAG)n, in addition to other genetic modifiers involved in the variability of the AAO, were first performed in Uruguay. We could replicate in our cohort the anticipation effect on the AAO by the ADORA2A rs5751876. Our results confirm the usefulness of an expanded molecular characterization in HD patients.

A novel mutation in the OAR domain of the ARX gene

Mutations in ARX gene should be considered in patients with mental disability or/and epilepsy. It is an X‐linked gene that has pleiotropic effects. Here, we report the case of a boy diagnosed with Ohtahara syndrome. We performed the molecular analysis of the gene and identified a new missense mutation.

Una nueva mutación en el promotor del gen del receptor de las lipoproteínas de baja densidad asociada a hipercolesterolemia familiar en homocigosis y heterocigosis

La hipercolesterolemia familiar (HF) es una enfermedad hereditaria, relativamente frecuente y asociada al desarrollo de ateroesclerosis y enfermedad coronaria prematuras. En este trabajo, describimos el hallazgo de una nueva mutacion (−47C>A) en la region promotora del gen del receptor de las lipoproteinas de baja densidad (rLDL), principal encargado de este fenotipo. Esta mutacion se identifico en una familia uruguaya con un fenotipo tipico de HF, en la cual aparecen individuos heterocigotos y homocigotos para la mutacion debido a la existencia de consanguinidad. El cambio nucleotidico ocurre en un sitio conservado y funcionalmente relevante del promotor; region en la que anteriormente se han descrito diversas mutaciones que provocan descensos drasticos en la actividad transcripcional del gen. No se han detectado otras variantes en las regiones analizadas del gen. Los analisis geneticos del rLDL asociados a otros genes de susceptibilidad permiten establecer un perfil genomico de riesgo cardiovascular, de aplicacion muy necesaria en el tratamiento clinico de familias con HF.

Deep sequencing discovery of causal mtDNA mutations in a patient with unspecific neurological disease

Mitochondrial diseases (MD) are a group of diseases that can be caused by either mutations in the mitochondrial genome or nuclear DNA. MD may be difficult to diagnose since very often they are highly heterogeneous and with overlapping phenotypes. Molecular genomics approaches, especially NGS have helped in this sense. In this study we have sequenced the mitochondrial genome of a girl with an unspecific neurological disorder and her mother. The later, while neurologically unaffected, suffers from a myopathy without clear cause. We were able to detect two non-synonymous mutations in the MT-ATP6 gene, which we propose are strong candidates for causative agents. 9017C as the main candidate present at high heteroplasmy frequency in the patient (83,2%) and moderate in the mother (45,4%) while it has a low frequency in the general population. It might act alone or in conjunction with 9010A as an accessory mutation. Evolutionary analysis showed that both mutations were located in a critical position in the F0 a subunit, from F0-F1 ATPase. Functional studies showed that carriers of those mutations in comparison to an unaffected individual (father) presented a decrease in the basal and ATP-dependent oxygen consumption rate and a decrease in the maximum respiration rate.