Genotype-phenotype discordance in a duchenne muscular dystrophy patient due to a novel mutation: Insights into the shock absorber function of dystrophin [Discordancia genotipo-fenotipo en un paciente con distrofia muscular de duchenne por una nueva mutaci�n: Hip�tesis de la funci�n de amortiguaci�n de la distrofina]

Introduction. Duchenne muscular dystrophy (DMD) is a genomic disorder characterized by progressive muscle wasting and weakness due to the absence or abnormal function of dystrophin; a protein that protects muscle cells from mechanical induced stress during contraction. Mutations in the DMD gene, may lead to different clinical phenotypes, collectively known as dystrophinopathies, of which DMD has the earliest onset and most severe progression. Case report. We report a novel deletion of exons 24-41, predicted to maintain the reading frame and expected to result in a mild phenotype. Conversely, the patient has a severe DMD phenotype. Conclusions. Our report supports the hypothesis that disruption of the gamma-actin-binding site located in the central rod domain plays a crucial role in the shock absorber function of dystrophin in muscle cells. Description of pathogenic variants in the DMD gene and the resulting phenotypes has important implications on the designing of molecular therapeutic approaches for DMD

Genotype-phenotype discordance in a duchenne muscular dystrophy patient due to a novel mutation: Insights into the shock absorber function of dystrophin [Discordancia genotipo-fenotipo en un paciente con distrofia muscular de duchenne por una nueva mutación: Hipótesis de la función de amortiguación de la distrofina]

Introduction. Duchenne muscular dystrophy (DMD) is a genomic disorder characterized by progressive muscle wasting and weakness due to the absence or abnormal function of dystrophin; a protein that protects muscle cells from mechanical induced stress during contraction. Mutations in the DMD gene, may lead to different clinical phenotypes, collectively known as dystrophinopathies, of which DMD has the earliest onset and most severe progression. Case report. We report a novel deletion of exons 24-41, predicted to maintain the reading frame and expected to result in a mild phenotype. Conversely, the patient has a severe DMD phenotype. Conclusions. Our report supports the hypothesis that disruption of the gamma-actin-binding site located in the central rod domain plays a crucial role in the shock absorber function of dystrophin in muscle cells. Description of pathogenic variants in the DMD gene and the resulting phenotypes has important implications on the designing of molecular therapeutic approaches for DMD

Improvements in the diagnosis of dystrophinopathies: What have we learnt in these last 20 years? [Mejoras en el diagnóstico de distrofinopatías: ¿Qué hemos aprendido después de 20 años?]

Introduction. Dystrophinopathies are X-linked genetic disorders caused by mutations in the DMD gene. Genetic tests are of utmost importance for management and genetic counseling of these diseases. However, the complexity of the DMD gene is a challenge for diagnosis. Aim. To describe recent advances in the diagnosis of dystrophinopathies, after 20 years since the firsts molecular assays for genetic screening for these diseases. Development. Currently, a variety of strategies such as automated mutation detection, cell-based methods and high throughput haplotyping have been developed to facilitate diagnosis of dystrophinopathies, carrier detection, prenatal and preimplantation diagnosis. Conclusion. New technologies have improved early detection and optimal management of dystrophinopathies and have established the basis for future molecular medicine. The most significant advances in dystrophinopathy diagnosis are reviewed herein. © 2011 Revista de Neurología

Analysis of polymorphisms and haplotypes in genes associated with vascular tone, hypertension and oxidative stress in Mexican-Mestizo women with severe preeclampsia

Objective: Several studies have reported the association of genes related to vascular tone, hypertension, oxidative stress and preeclampsia. We investigated the possible association among three polymorphisms in eNOS (as well their haplotypes): one of MTHFR, one of GSTP1 and one of AGT, with severe preeclampsia in Mexican-Mestizo women. Methods: Two hundred thirty women with severe preeclampsia and 350 control subjects were genotyped; for rs2070744 and rs1799983 of eNOS, rs1801133 of MTHFR, rs1695 of GSTP1 and rs699 of AGT we used real-time PCR allelic discrimination and for VNTR of eNOS, PCR. Allele frequency differences were assessed by ?2. Logistic regression was used to test for associations and for haplotype frequencies using Haploview 4.2. Results: Genotypic and allelic distribution of the polymorphisms was similar between cases and controls; likewise, haplotype frequencies of the three polymorphisms of eNOS did not differ significantly. Conclusions: To our knowledge, this is the first time that these polymorphisms have been analyzed together and exclusively in women with severe preeclampsia. However, we did not find an association between polymorphisms of eNOS, MTHFR, GSTP1 and AGT with severe preeclampsia in our population. Additionally, we observed differences in the distribution of the alleles and genotypes of these polymorphisms in our population in comparison to those described in other ethnic groups. Zapotitlán 2013 The Canadian Society of Clinical Chemists

Origin of oligodendrocytes in the subventricular zone of the adult brain

Background: CODIS-STRs in Native Mexican groups have rarely been analysed for human identification and anthropological purposes. Aim: To analyse the genetic relationships and population structure among three Native Mexican groups from Mesoamerica. Subjects and methods: 531 unrelated Native individuals from Mexico were PCR-typed for 15 and 9 autosomal STRs (Identifiler® and Profiler® kits, respectively), including five population samples: Purépechas (Mountain, Valley and Lake), Triquis and Yucatec Mayas. Previously published STR data were included in the analyses. Results: Allele frequencies and statistical parameters of forensic importance were estimated by population. The majority of Native groups were not differentiated pairwise, excepting Triquis and Purépechas, which was attributable to their relative geographic and cultural isolation. Although Mayas, Triquis and Purépechas-Mountain presented the highest number of private alleles, suggesting recurrent gene flow, the elevated differentiation of Triquis indicates a different origin of this gene flow. Interestingly, Huastecos and Mayas were not differentiated, which is in agreement with the archaeological hypothesis that Huastecos represent an ancestral Maya group. Interpopulation variability was greater in Natives than in Mestizos, both significant. Conclusion: Although results suggest that European admixture has increased the similarity between Native Mexican groups, the differentiation and inconsistent clustering by language or geography stresses the importance of serial founder effect and/or genetic drift in showing their present genetic relationships. " 2010 Informa UK, Ltd.",,,,,,"10.3109/03014461003743801",,,"http://hdl.handle.net/20.500.12104/43429","http://www.scopus.com/inward/record.url?eid=2-s2.0-77958527932&partnerID=40&md5=26ac2642334bd714216324c0038e780

Association of the rs1801133 variant in the MTHFR gene and sporadic Parkinson's disease

The MTHFR gene has been reported as a susceptibility locus for sporadic Parkinson's disease (sPD). The functional variant rs1801133 has been linked to hyperhomocysteinemia and dopaminergic cell death. Among different populations, Mexican-Mestizos (most present-day Mexicans) have the highest frequency of this variant. Therefore, we sought to determine a possible association of rs1801133 with SPD. In total, 356 individuals were included: 140 pa tients with PD, diagnosed according to the Queen Square Brain Bank criteria, and 216 neurologically healthy controls. Genotyping was performed using TaqMan probes for rs1801133 and real-time PCR. Logistic regression analysis with adjustment for smoking and gender was used to test for an association between genotype and SPD. The CC genotype was associated with SPD; exp(?) = 2.06; 95% CI: 1.101-3.873, p = 0.024. No association with age at onset, cognitive impairment or gender was found in our study group. Our data suggest an important role of MTHFR gene variants in SPD

Analysis of polymorphisms in interleukin-10, interleukin-6, and interleukin-1 receptor antagonist in Mexican-Mestizo women with pre-eclampsia

Due to the fact that studies seeking associations of polymorphisms in regulatory regions of cytokine genes with pre-eclampsia (PE) have not always been consistent in different population analyses, the aim of this study was to investigate the possible association between rs1800896 of interleukin-10 (IL-10), rs1800795 of interleukin-6 (IL-6), and the variable number of tandem repeats (VNTR) in intron 2 of interleukin-1 receptor antagonist (IL-1Ra), as well as gene-gene interactions between these three polymorphisms with the presence of PE in Mexican-Mestizo women and one Amerindian population from México (Maya). A case-control study was performed where 411 pre-eclamptic cases and 613 controls were genotyped. For the rs1800896 of IL-10 and rs1800795 of IL-6, we used real-time polymerase chain reaction (PCR) allelic discrimination and for the VNTR of IL-1Ra, PCR. Allele frequency differences were assessed by Chi-squared test; logistic regression was used to test for associations; a gene-gene interaction was conducted. Genotypic and allelic distribution of the polymorphisms was similar in our population. The estimated of the gene-gene interaction between the polymorphisms did not differ significantly. However, we observed important differences in the distribution of the alleles and genotypes of the three polymorphisms analyzed between Mestiza-Mexicanas and Maya-Mestizo women. In conclusion, we did not find an association between polymorphisms in IL-10, IL-6, and IL-1Ra and PE in Mexican-Mestizo and Maya-Mestizo women. To our knowledge, this is the first time that these three polymorphisms were analyzed together with gene-gene interaction in women with PE. Zapotitlán 2012, Mary Ann Liebert, Inc

Duchenne muscular dystrophy in a developing country: Challenges in management and genetic counseling

Background and objective: Multidisciplinary management of Duchenne Muscular Dystrophy (DMD) has achieved outstanding results in developed nations. We aimed to describe the status of diagnosis and management of DMD in a developing country through the experience of non-profit organizations. Methods: A Multistate, multiple-source, population-based survey was performed from medical records of 432 patients. Data were retrospectively collected, reviewed and curated by health specialists; including clinical features, age at first symptoms, age at diagnosis, disease progression and management, family history, education, age and cause of death. Results: There is a delay in noticing first symptoms and it did not diminish over the past 20 years. Less than 30% of patients obtained definite diagnosis and most of them are in physiotherapy programs but not under steroid treatment. In our study, family history does not anticipate recognition of symptoms compared to sporadic cases (p=0.05). Approximately 93.33% of our patients attended to education programs. Mean age at death was 18.94 ± 6.73 years and the most frequent cause was pneumonia. Conclusion: Delayed diagnosis of DMD in Mexico is mainly caused by the late detection of first symptoms. There is no difference in early detection of symptoms between familiar and sporadic cases. Lifespan of patients in our cohort is reduced compared to developed countries. The late diagnosis and low percentage of definite cases may affect patient management and genetic counseling and could also preclude participation of patients into novel clinical trials

Duchenne muscular dystrophy in a developing country: Challenges in management and genetic counseling

Background and objective: Multidisciplinary management of Duchenne Muscular Dystrophy (DMD) has achieved outstanding results in developed nations. We aimed to describe the status of diagnosis and management of DMD in a developing country through the experience of non-profit organizations. Methods: A Multistate, multiple-source, population-based survey was performed from medical records of 432 patients. Data were retrospectively collected, reviewed and curated by health specialists; including clinical features, age at first symptoms, age at diagnosis, disease progression and management, family history, education, age and cause of death. Results: There is a delay in noticing first symptoms and it did not diminish over the past 20 years. Less than 30% of patients obtained definite diagnosis and most of them are in physiotherapy programs but not under steroid treatment. In our study, family history does not anticipate recognition of symptoms compared to sporadic cases (p=0.05). Approximately 93.33% of our patients attended to education programs. Mean age at death was 18.94 Zapotitlán 6.73 years and the most frequent cause was pneumonia. Conclusion: Delayed diagnosis of DMD in Mexico is mainly caused by the late detection of first symptoms. There is no difference in early detection of symptoms between familiar and sporadic cases. Lifespan of patients in our cohort is reduced compared to developed countries. The late diagnosis and low percentage of definite cases may affect patient management and genetic counseling and could also preclude participation of patients into novel clinical trials