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- ÍtemAcceso Abierto
Creating and validating a warfarin pharmacogenetic dosing algorithm for colombian patients(2018) Galvez, Jubby Marcela; Restrepo Fernández, Carlos Martín; Contreras Bravo, Nora Constanza; Alvarado, Clara; Calderón Ospina, Carlos Alberto; Peña, Nidia; Cifuentes, Ricardo A; Duarte, Daniela; Laissue, Paul; Fonseca Mendoza, Dora JanethPurpose: Warfarin is an oral anticoagulant associated with adverse reaction to drugs due to wide inter-and intra-individual dosage variability. Warfarin dosage has been related to non-genetic and genetic factors. CYP2C9 and VKORC1 gene polymorphisms affect warfarin metabolism and dosage. Due to the central role of populations’ ethnical and genetic origin on warfarin dosage variability, novel algorithms for Latin American subgroups are necessary to establish safe anticoagulation therapy. Patients and methods: We genotyped CYP2C9*2 (c.430C and gt; T), CYP2C9*3 (c.1075A and gt; C), CYP4F2 (c.1297G and gt; A), and VKORC1 (-1639 G and gt; A) polymorphisms in 152 Colombian patients who received warfarin. We evaluated the impact on the variability of patients’ warfarin dose requirements. Multiple linear regression analysis, using genetic and non-genetic variables, was used for creating an algorithm for optimal warfarin maintenance dose. Results: Median weekly prescribed warfarin dosage was significantly lower in patients having the VKORC1-1639 AA genotype and poor CYP2C9*2/*2,*2/*3 metabolizers than their wild-type counterparts. We found a 2.3-fold increase in mean dose for normal sensitivity patients (wild-type VKORC1/CYP2C9 genotypes) compared to the other groups (moderate and high sensitivity); 31.5% of the patients in our study group had warfarin sensitivity-related genotypes. The estimated regression equation accounted for 44.4% of overall variability in regard to warfarin maintenance dose. The algorithm was validated, giving 45.9% correlation (R 2 =0.459). Conclusion: Our results describe and validate the first algorithm for predicting warfarin maintenance in a Colombian mestizo population and have contributed toward the understanding of pharmacogenetics in a Latin American population subgroup. © 2018 Galvez et al. - ÍtemAcceso AbiertoCITED2 mutations potentially cause idiopathic premature ovarian failure(2012) Fonseca Mendoza, Dora Janeth; Ojeda, Diego; Lakhal, Besma; Braham, Rim; Eggers, Stefanie; Turbitt, Erin; White, Stefan; Grover, Sonia; Warne, Garry; Zacharin, Margaret; Lam, Alexandra Nevin; Landolsi, Hanène; Elghezal, Hatem; Saâd, Ali; Restrepo Fernández, Carlos Martín; Fellous, Marc; Sinclair, Andrew; Koopman, Peter; Laissue, PaulAnomalies in gonadal development in a mouse knockout model of Cited2 have been recently described. In Cited2 -/- female gonads, an ectopic cell migration was observed and the female program of sex determination was transiently delayed. We hypothesize that, in humans, this temporary inhibition of genes should be sufficient to provoke a developmental impairment of the female gonads, conducive to premature ovarian failure (POF). To establish whether CITED2 mutations are a common cause of the disease, we performed a mutational analysis of this gene in a panel of patients with POF and in a group of control women with normal fertility. We amplified and directly sequenced the complete open reading frame of CITED2 in 139 patients with POF and 290 controls. This study revealed 5 synonymous and 3 nonsynonymous variants. Among these, 7 are novel. The nonsynonymous variant c.604C and gt;A (p.Pro202Thr) was found uniquely in 1 woman from the POF group. In silico analysis of this mutation indicated a potential deleterious effect. We conclude that mutations in CITED2 may be involved in POF pathogenesis. © 2012 Mosby, Inc. All rights reserved.
- ÍtemAcceso AbiertoSequence analysis of the ADRA2A coding region in children affected by attention deficit hyperactivity disorder(2013) Castro, Taryn; Mateus, Heidi Eliana; Fonseca Mendoza, Dora Janeth; Forero, Diego; Restrepo Fernández, Carlos Martín; Talero Gutiérrez, Claudia; Vélez van Meerbeke, Alberto Francisco; Laissue, PaulAttention deficit hyperactivity disorder (ADHD) is a common neurobehavioral pathology characterized by distinct degrees of inattention, hyperactivity and impulsivity. Although ADHD etiology remains elusive, the ADRA2A candidate gene underlies a particular interest, since it participates in the prefrontal cortex regulation of executive function. Three SNPs located on 5? and 3?UTR regions of the gene have been extensively explored but none of them have been definitely validated as a predisposition or a causative sequence variation. In this study, in order to determine whether ADRA2A non-synonymous sequence variants, resulting in biochemical modifications of the protein, are a common cause of the disease we sequenced the complete ADRA2A coding region in a panel of ADHD children of Colombian origin. We identified the c.1138 C>A (p.Arg380Arg) silent substitution. We conclude that ADRA2A non-synonymous sequence variants do not cause ADHD in our sample population. We cannot formerly discard a potential role of this gene during ADHD pathogenesis since only the coding region was analysed. We hope that these results will encourage further researchers to sequence the promoter and coding regions of ADRA2A in large panels of ADHD patients from distinct ethnical origins. © 2013 Springer-Verlag Italia.
- ÍtemAcceso AbiertoEvidence of an association between 10/10 genotype of DAT1 and endophenotypes of attention deficit/hyperactivity disorder(2015) Agudelo, J.A.; Gálvez, J.M.; Fonseca Mendoza, Dora Janeth; Mateus Arbelaez, Heidi Eliana; Talero Gutiérrez, Claudia; Vélez van Meerbeke, Alberto FranciscoIntroducción: La variancia genética del trastorno por déficit de atención e hiperactividad (TDAH) es determinante para el fenotipo. La repetición en tándem en número variable (VNTR) de 40 pares de bases (pb) en la región no traducida 3 (UTR) del gen DAT1 se ha asociado ala susceptibilidad de presentar TDAH debido al incremento de expresión del transportador de dopamina. Objetivo: Determinar la asociación entre el VNTR del DAT1 y el fenotipo y/o endofenotipos del TDAH en una muestra de ninos ˜ de 6 a 15 anos ˜ de la ciudad de Bogotá. Sujetos y métodos: Se seleccionó a 73 pacientes con TDAH y 54 controles. En todos los individuos se realizó una prueba de WISC y se valoraron las funciones ejecutivas. Mediante reacción en cadena de la polimerasa se amplificó el VNTR de DAT1. Se establecieron estadísticos genéticopoblacionales, análisis de asociación y correlación entre las pruebas neuropsicológicas y el genotipo. Resultados: El polimorfismo del DAT1 no mostró asociación con TDAH (p = 0,85). Sin embargo, el genotipo 10/10 evidenció asociación con el índice de velocidad de procesamiento (p < 0,05). En el subtipo hiperactividad hubo correlación genotípica con subpruebas de la función ejecutiva (flexibilidad cognitiva) (p ≤ 0,01). En el subgrupo mixto, el genotipo 10/10 se asoció al índice de comprensión verbal del WISC (p < 0,05). Conclusiones: Se encontró una correlación entre el genotipo del VNTR de DAT1 con la subprueba «índice de velocidad de procesamiento» del WISC y la subprueba «flexibilidad cognitiva» de la función ejecutiva. Este es el primer reporte que evalúa el gen DAT1 en población colombiana con TDAH.
- ÍtemAcceso AbiertoCarrier frequency of F508del mutation of cystic fibrosis in medical students from Universidad del Rosario, Bogotá, Colombia(2007) Mateus H.E.; Fonseca Mendoza, Dora Janeth; Sanchez L.S.; Peñaloza I.F.; Forero D.V.; Perdomo P.A.; Quiasua D.C.; Ramírez A.; Montoya L.C.; Pérez L.A.; Amado H.P.; Molano J.A.; Amaya S.A.; Duran M.H.; Cárdenas V.C.; Guevara K.; Parga D.A.; Esparrogosa C.L.Introduction: Cystic fibrosis (CF) is the most frequent autosomical recessive disorder in Caucasian population with an incidence of in 2000 newborns. The disease is caused by mutations in the cfr gene, but the most common mutation is F508del, which accounts for 66% of CF chromosomes worldwide and a carrier frequency for Caucasian population of 1 in 25. Objective: To determine the carrier frequency of the F508del mutation in 110 unrelated, healthy students from the Facultad de Medicina, Universidad del Rosario. Methods. The presence of F508del mutation using PCR and heteroduplex analysis was determined. Results: Only four heterozygotes for F508del mutation were discovered. This represents a carrier frequency of 1 in 27 students. Conclusions: This estimated frequency of F508del carriers is higher than expected, encouraging further'screening in normal control individuals from different regions of Colombia. © 2007 Corporación Editora Médica del Valle.
- ÍtemAcceso AbiertoCarrier detection of Duchenne muscular dystrophy in Colombia families by microsatellite analysis(2008) Fonseca Mendoza, Dora Janeth; Silva C.T.; Mateus H.Introduction: The muscular dystrophies of Duchenne and Becker are X-linked recessive neuromuscular disorders; the carrier testing protocols include mutation detection or linkage analysis. Objective: The aim of this investigation was to use the segregation analysis of STR loci to determine the carrier status in 37 families with DMD/DMB. Methods: From 37 families 174 individuals were studied through segregation of 10 intra and extragenic shorttandem repeats (STR) in the members of the family. Results: The carrier status of 89.2% women of the tested group could be assigned by linkage analysis, 65.7% carriers and 23.5% non-carriers Conclusions: Linkage analysis was proven to be a powerful tool for the carrier detection in DMD/BMD and should be taken into account in genetic counselling practice. © 2008 Corporación Editora Médica del Valle.
ÍtemSolo MetadatosEvidence of association between SNAP25 gene and attention deficit hyperactivity disorder in a Latin American sample(2014) Gálvez, Jubby M.; Garzon-Forero, Diego A; Fonseca Mendoza, Dora Janeth; Mateus, Heidi E.; Talero Gutiérrez, Claudia; Vélez van Meerbeke, Alberto FranciscoAttention deficit hyperactivity disorder (ADHD) is one of the most highly heritable behavioral disorders in childhood, with heritability estimates between 60 and 90 %. Family, twin and adoption studies have indicated a strong genetic component in the susceptibility to ADHD. The synaptosomal-associated protein of molecular weight 25 kDa (SNAP25) is a plasma membrane protein known to be involved in synaptic and neural plasticity. Animal model studies have shown that SNAP25 gene is responsible for hyperkinetic behavior in the coloboma mouse. In recent studies, several authors reported an association between SNAP25 and ADHD. In this study, we used a case-control approach to analyze the possible association of two polymorphisms of SNAP25 for possible association with ADHD in a sample of 73 cases and 152 controls in a Colombian children population. Polymorphisms are located in 3? untranslated region of SNAP25, positions T1065G and T1069C. We found a significant association with the GT haplotype (rs3746554{pipe}rs1051312) of SNAP25 (p = 0.001). Evidence of association was also found for the G/G genotype of rs3746554 (p = 0.002) and C/C genotype of rs1051312 (p = 0.009). This is the first study in a Latin American population. Similar to other studies, we found evidence of the association of SNAP25 and ADHD. © 2013 Springer-Verlag Wien.- ÍtemSolo MetadatosA novel TGM1 mutation, leading to multiple splicing rearrangements, is associated with autosomal recessive congenital ichthyosis(2015) Ortega?Recalde, O.; Moreno, M. B.; Vergara, J. I.; Fonseca Mendoza, Dora Janeth; Rojas, R. F.; Mosquera, H.; Medina, C. L.; Restrepo Fernández, Carlos Martín; Laissue, P.Summary Autosomal recessive congenital ichthyosis (ARCI) is a group of rare, clinically heterogeneous skin disorders that affect cornification. ARCI includes lamellar ichthyosis, congenital ichthyosiform erythroderma and harlequin ichthyosis. TGM1 mutations cause > 50% of ARCI cases in the USA. We report two siblings with ARCI. They were found to carry a novel aetiological TGM1 mutation, which leads to the synthesis of multiple abnormal transcripts. These molecules resulted from three independent mechanisms: intron retention, exon skipping and activation of expand cryptic splice sites. Taken together, our findings expand the known TGM1 mutation repertoire, and provide an insight into the molecular mechanisms leading to ARCI phenotypes. These results could be useful for genetic counselling and future potential genotype-phenotype correlations. © 2015 British Association of Dermatologists.
- ÍtemSolo MetadatosA novel familial case of diffuse leukodystrophy related to NDUFV1 compound heterozygous mutations(2013) Ortega-Recalde, Oscar; Fonseca Mendoza, Dora Janeth; Patiño, Liliana Catherine; Atuesta, Juan Jaime; Rivera-Nieto, Carolina; Restrepo Fernández, Carlos Martín; Mateus, Heidi Eliana; van der Knaap, Marjo S.; Laissue, PaulNDUFV1 mutations have been related to encephalopathic phenotypes due to mitochondrial energy metabolism disturbances. In this study, we report two siblings affected by a diffuse leukodystrophy, who carry the NDUFV1 c.1156C>T (p.Arg386Cys) missense mutation and a novel 42-bp deletion. Bioinformatic and molecular analysis indicated that this deletion lead to the synthesis of mRNA molecules carrying a premature stop codon, which might be degraded by the nonsense-mediated decay system. Our results add information on the molecular basis and the phenotypic features of mitochondrial disease caused by NDUFV1 mutations. © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
- ÍtemAcceso AbiertoSequence analysis of the CDKN1B gene in patients with premature ovarian failure reveals a novel mutation potentially related to the phenotype(2011) Ojeda D.; Lakhal B.; Fonseca Mendoza, Dora Janeth; Braham R.; Landolsi H.; Mateus H.E.; Restrepo Fernández, Carlos Martín; Elghezal H.; Saâd A.; Laissue P.Earlier reports demonstrated a key role of Cdkn1b during mouse ovarian development. In this study, the sequencing analysis of the complete coding region of this gene in a panel of premature ovarian failure patients and control subjects reveals a novel mutation potentially related to the phenotype. © 2011 by American Society for Reproductive Medicine.
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