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ÍtemSolo MetadatosAnálisis de microdeleciones en 22q11 en pacientes colombianos con cardiopatía congénita no sindrómica.(2011-12) Salazar, Marleny; Villalba, Guiovanny; Mateus, Heidi; Villegas Gálvez, Victoria Eugenia; Fonseca Mendoza, Dora Janeth; Nuñez, Federico; Caicedo, Victor; Pachon, Sonia; Bernal, JaimeLos defectos cardiacos conforman las malformaciones congénitas más frecuentes, con una incidencia que se ha estimado entre 4 y 12 por 1000 en recién nacidos vivos. Estos tienen una etiología multifactorial en la que convergen la predisposición genética y los factores ambientales. A partir de 1990 se ha relacionado este tipo de patologías con microdelección 22q11. Se determinó la frecuencia de la microdeleción 22q11 en pacientes con cardiopatía congénita no sindrómica. Se analizaron 61 pacientes con cardiopatía congénita, a partir de ADN de sangre periférica y posterior amplificación, mediante PCR multiplex del gen TUPLE1 y del STR D10S2198, visualización electroforesis en geles de agarosa y análisis densitométrico para determinar dosis génica. Se encontraron 3 pacientes con microdeleción 22q11, para una frecuencia de 4,9%. Esta microdeleción se asoció en dos de los casos a Tetralogía de Fallot y en el otro a Defecto Septal Atrial (DSA). En conclusión, la frecuencia de microdeleción 22q11 en la población analizada es de 4,9%. Dentro de los casos de Tetralogía de Fallot, la microdeleción estaba presente en el 7,4% y en los DSA corresponde al 11,1%.- ÍtemSolo MetadatosTranscriptomic analysis of FUCA1 knock-down in keratinocytes reveals new insights into the pathogenesis of fucosidosis skin lesions(2018) Valero-Rubio D.; Jiménez K.M.; Fonseca Mendoza, Dora Janeth; Payan-Gomez, Cesar; Laissue P.Fucosidosis is a rare lysosomal storage disease which has been classified into two subtypes, depending on the severity of clinical signs and symptoms. Fucosidosis patients’ skin abnormalities include angiokeratoma corporis diffusum, widespread telangiectasia, thick skin, hyperhidrosis and hypohidrosis, acrocyanosis and distal transverse nail bands. It has been described that >50% of fucosidosis patients have angiokeratoma. At molecular level, fucosidosis is caused by lysosomal alpha-L-fucosidase (FUCA1) gene mutations. Obtaining samples for functional studies has been challenging due to the inherent difficulty in finding affected individuals. The effect of FUCA1 dysfunction on gene expression is unknown. The aim of this study was to analyse, in keratinocytes, the transcriptomic effect of FUCA1 knock-down for a better understanding of skin lesions’ pathogenesis affecting fucosidosis patients. FUCA1 knock-down (siRNA) was performed in human HaCaT immortalised keratinocytes. Affymetrix arrays and qPCR were used for analysing gene expression. Bioinformatics was used for functional clustering of modified genes. In total, 387 genes showed differential expression between FUCA1 silenced and non-silenced cells (222 up-regulated and 165 down-regulated). Up-regulated genes belonged to two major groups: keratinocyte differentiation/epidermal development (n = 17) and immune response (n = 61). Several transcription factors were up-regulated in FUCA1-siRNA transfected cells. This effect might partly have been produced by abnormal transcription factor expression, that is FOXN1. We thus propose that fucosidosis-related skin lesions (eg angiokeratoma) and those of other diseases (eg psoriasis) might be caused by dysfunctions in common aetiological overlapping molecular cascades. © 2018 John Wiley and Sons A/S. Published by John Wiley and Sons Ltd
- 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 MetadatosIdentification and functional characterization of GAA mutations in Colombian patients affected by pompe disease(2013) Niño, Mónica Yasmín; Mateus, Heidi Eliana; Fonseca Mendoza, Dora Janeth; Kroos, Marian A.; Ospina, Sandra Yaneth; Mejía, Juan Fernando; Uribe, Jesús Alfredo; Reuser, Arnold J. J.; Laissue, PaulPompe disease (PD) is a recessive metabolic disorder characterized by acid ?-glucosidase (GAA) deficiency, which results in lysosomal accumulation of glycogen in all tissues, especially in skeletal muscles. PD clinical course is mainly determined by the nature of the GAA mutations. Although ~400 distinct GAA sequence variations have been described, the genotype-phenotype correlation is not always evident. In this study, we describe the first clinical and genetic analysis of Colombian PD patients performed in 11 affected individuals. GAA open reading frame sequencing revealed eight distinct mutations related to PD etiology including two novel missense mutations, c.1106 T > C (p.Leu369Pro) and c.2236 T > C (p.Trp746Arg). In vitro functional studies showed that the structural changes conferred by both mutations did not inhibit the synthesis of the 110 kD GAA precursor form but affected the processing and intracellular transport of GAA. In addition, analysis of previously described variants located at this position (p.Trp746Gly, p.Trp746Cys, p.Trp746Ser, p.Trp746X) revealed new insights in the molecular basis of PD. Notably, we found that p.Trp746Cys mutation, which was previously described as a polymorphism as well as a causal mutation, displayed a mild deleterious effect. Interestingly and by chance, our study argues in favor of a remarkable Afro-American and European ancestry of the Colombian population. Taken together, our report provides valuable information on the PD genotype–phenotype correlation, which is expected to facilitate and improve genetic counseling of affected individuals and their families. © SSIEM and Springer-Verlag Berlin Heidelberg 2012.
- 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.
- ÍtemSolo MetadatosPossible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy(2020) Calderón Ospina, Carlos Alberto; Galvez, J. M.; López-Cabra, C.; Morales. N.; Restrepo Fernández, Carlos Martín; Rodríguez, J.; Aristizábal-Gutiérrez, F. A.; Vélez van Meerbeke, Alberto Francisco; Laissue, P.; Fonseca Mendoza, Dora JanethBackground: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality. Objective: Our objective was to assess the impact of some genetic factors and its possible association with treatment response and adverse drug reactions (ADRs) to phenytoin in 67 adult Colombian patients with epilepsy. Methods: We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: CYP2C9*2-c.430C>T (rs1799853), CYP2C9*3-c.1075A>C (rs1057910), ABCB1-c.3435T>C (rs1045642), and SCN1A-IVS5-91G>A (rs3812718), and their association with treatment response. Patients were followed for 1 year to confirm the existence of DRE (non-response) and ADRs using an active pharmacovigilance approach, followed by a consensus in order to classify ADRs according to causality, preventability, intensity and their relation with phenytoin dose, the duration of treatment, and susceptibility factors (DoTS methodology). Results: A little more than half of evaluated subjects (52.2%) were non-responding to phenytoin. Regarding the genotype-phenotype correlation there was no association between polymorphisms of SCN1A and ABCB1 and DRE (non-response) (p = 0.34), and neither with CYP2C9 polymorphisms and the occurrence of ADRs (p = 0.42). We only found an association between polymorphic alleles of CYP2C9 and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (p = 0.001). Alleles CYP2C9*2-c.430C>T and CYP2C9*3-c.1075A>C were identified as susceptibility factors to ADRs in 24% of patients. Conclusions: Decreased function alleles of CYP2C9 were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (p = 0.001). However, the genetic variants CYP2C9*2-c.430C>T, CYP2C9*3-c.1075A>C, ABCB1-c.3435T>C, and SCN1A-IVS5-91G>A, were not associated with treatment response in our study. © Copyright © 2020 Calderon-Ospina, Galvez, López-Cabra, Morales, Restrepo, Rodríguez, Aristizábal-Gutiérrez, Velez-van-Meerbeke, Laissue and Fonseca-Mendoza.
- ÍtemSolo MetadatosColombian results of the interlaboratory Quality Control Exercise 2009-2010(2011) Builes,J.J.; Aguirre, D.; A. Manrique; Puerto, Y.; Bravo, M.L.; Gaviria, A.; Gutierrez, A.; Muñoz, M.; Fonseca Mendoza, Dora Janeth; Usaquen, W.; Castillo, A.; Pineda, C.; Ugalde, N.Colombian Reference National Laboratory, GENES LTDA, have organized and coordinated for the past two years (2009 and 2010) the Quality Control Exercise for laboratories undertaking paternity, maternity and forensic tests with DNA markers. Twenty-two laboratories have participated in 2009, increasing the number to 27 in 2010. Laboratories in Colombia, Brazil, Ecuador, Peru, Dominican Republic and Panama have participated in these exercises. There have been some similarities in the two controls: A practical exercise, three blood samples on FTA cards were sent to each participating laboratory to be genotyped for DNA markers using the routine methodologies in their laboratories; theoretical exercises including optional and obligatory cases. For the theoretical exercises, the participating laboratories should calculate the partial and final PI or BRI (Biological Relationship Index or Paternity Index). Forty-nine and 52 markers were under consensus for 2009 and 2010, respectively, distributed in autosomal, Y and X chromosomes STR. With respect to 2008, 12 and 15 additional markers were under consensus for 2009 and 2010, respectively. The rate of reporting error was 2.9% in 2009 while in 2010, 4.7% error was reported. The Proficiency Test conducted through the Colombian National Reference Laboratory has become a useful tool for quality assurance of all Colombian laboratories and some of Latin America that do DNA testing to establish biological relationships and an excellent opportunity for ongoing training of experts from the region.
- ÍtemSolo MetadatosIdentificación de Mutaciones puntuales del gen de la 21-hidroxilasa en pacientes afectados con hiperplasia suprarrenal congenita(2005-06-01) Fonseca Mendoza, Dora Janeth; Gutierrez, Andrés; Silva, Claudia T.; Coll, Mauricio; Malo, Gustavo; Orjuela, Camilo; Arteaga, Clara; Giraldo, AlejandroIntroducción: La hiperlasia suprarrenal congenita es un trastorno autosomico recesivo debido a la inadecuada secreción de cortisol. Más del 95% de los casos de hiperplasia suprarrenal congenita son causados por defectos del gen de la 21 hidroxilasa, CYP21A2. Las manifestaciones clinicas incluyen la forma clasica y la forma no clasica. Objetivos: determinar la frecuencia de las mutaciones puntuales P30L, IVS2-12A/C-G,del 8pb, I172N, cluster Ex 6, V281L, Q318X,R356W y P453S en pacientes con hiperplasia suprarrenal congenita. Materiales y metodos: Se estudiaron 58 pacientes, de los cuales, 48 fueron clasicos y 10 no clasicos. Mediante PCR alelo-especifica y ACRS (Amplified Creation Restriction Sites), se analizaron 9 mutaciones puntuales del gen CYP21A2 y se determino la frecuencia en la población analizada. Resultados. Los alelos afectados se identificaron en el 82,8% de los cromosomas. Las mutaciones mas frecuentes fueron: IVS2-12A/C-G (26,7%),Q318X(21-5%), V281L (12,1%) e I172N (12,15). Conclusiones: Las mutaciones mas frecuentes en Colombia son similares a las de otros paises del mundo, exepto para Q318X que presento una mayor frecuencoa, pero similar a la de otros paises latinoamericanos. Este hallazgo y la existencia de 17,2% de alelos no identificados puede indicar diferencia entre el acervo genetico de las poblaciones. En la forma clasica perdedora de la sal predominaron las mutaciones Q318X e IVS2-A12/C-G; en la virilizante simple, IVS2-12A/C-G e I172N y en la no clasica, V281L, lo cual esta relaiconado con el grado de actividad enzimatica. En la forma no clasica, se encontraron alelos severos en el 66,7% de los casos, lo que determina el riesgo de tener hijos afectados con la forma grave virilizante simple o perdedora de sal. Los resultados reportados permiten ofrecer asesoramiento genetico y diagnostico personal.
- ÍtemSolo MetadatosProstaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis(2012) Diggle, Christine P.; Parry, David A.; Logan, Clare V.; Laissue, Paul; Rivera, Carolina; Restrepo Fernández, Carlos Martín; Fonseca Mendoza, Dora Janeth; Morgan, Joanne E.; Allanore, Yannick; Fontenay, Michaela; Wipff, Julien; Varret, Mathilde; Gibault, Laure; Dalantaeva, Nadezhda; Korbonits, Márta; Zhou, Bowen; Yuan, Gang; Harifi, Ghita; Cefle, Kivanc; Palanduz, Sukru; Akoglu, Hadim; Zwijnenburg, Petra J.; Lichtenbelt, Klaske D.; Aubry?Rozier, Bérengère; Superti?Furga, Andrea; Dallapiccola, Bruno; Accadia, Maria; Brancati, Francesco; Sheridan, Eamonn G.; Taylor, Graham R.; Carr, Ian M.; Johnson, Colin A.; Markham, Alexander F.; Bonthron, David T.Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E2 (PGE2) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE2, but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE2 metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity. © 2012 Wiley Periodicals, Inc.
