(-)-Epicatechin modulates the expression of myomiRs implicated in exercise response in mouse skeletal muscle.

The flavanol (-)-epicatechin has exercise-mimetic properties. Besides, several miRNAs play a role in modulating the adaptation of the muscle to different training protocols. However, notwithstanding all information, few studies aimed to determine if (-)-epicatechin can modify the expression of miRNAs related to skeletal muscle development and regeneration. Mice were treated for fifteen days by oral gavage with the flavanol (-)-epicatechin. After treatment, the quadriceps of the mice was dissected, and total RNA was extracted. The expression level of miR-133, -204, -206, -223, -486, and -491 was analyzed by qRT-PCR. We also used bioinformatic analysis to predict the participation of these miRNAs in different skeletal muscle signal transduction pathways. Additionally, we analyzed the level of the myogenic proteins MyoD and myogenin by Western blot and measured the cross-sectional area of muscle fibers stained with E&H. (-)-Epicatechin upregulated the expression of miR-133, -204, -206, -223, and -491 significantly, which was associated with an increase in the level of the myogenic proteins MyoD and Myogenin and an augment in the fiber size. The bioinformatics analysis showed that the studied miRNAs might participate in different signal transduction pathways related to muscle development and adaptation. Our results showed that (-)-epicatechin upregulated miRNAs that participate in skeletal exercise muscle adaptation, induced muscle hypertrophy, and increased the level of myogenic proteins MyoD and MyoG.

(-) - Epicatechin improves Tibialis anterior muscle repair in CD1 mice with BaCl2-induced damage.

Several studies have shown the beneficial effect that Epicatechin (Epi) has on the skeletal muscle of murine models and patients with muscular dystrophy and in the muscles of patients with diabetes or murine sarcopenia models. This flavanol has been shown to enhance antioxidant pathways and improve muscle architecture. However, the repair process during muscle regeneration has not been analyzed. To address this, we characterize the effect of Epi in the repair process of the Tibialis anterior in a murine model with BaCl2-induced damage. CD1 mice of 10 weeks of age were randomly selected and injured with BaCl2. One hour later, they were divided into four groups (n=6 for histology groups and n=12 for western blot groups). Epi was administered every 12h, until the time of sacrifice. Histological and morphological analysis showed that Epi significantly reduced the area of damage and hypertrophy at 15 days in the damaged muscle. Furthermore, western blot assays showed that the treatment increases ß-catenin (active) and myogenic proteins such as MyoD and Myogenin. These results show that Epi exerts therapeutic effects accelerating skeletal muscle repair after induced damage chemically, thus highlighting the therapeutic potential of this flavanol in different myopathies.

Lack of Delta-Sarcoglycan (Sgcd) Results in Retinal Degeneration.

Age-related macular degeneration (AMD) is the leading cause of central vision loss and severe blindness among the elderly population. Recently, we reported on the association of the SGCD gene (encoding for δ-sarcoglycan) polymorphisms with AMD. However, the functional consequence of Sgcd alterations in retinal degeneration is not known. Herein, we characterized changes in the retina of the Sgcd knocked-out mouse (KO, Sgcd-/-). At baseline, we analyzed the retina structure of three-month-old wild-type (WT, Sgcd+/+) and Sgcd-/- mice by hematoxylin and eosin (H&E) staining, assessed the Sgcd-protein complex (α-, ß-, γ-, and ε-sarcoglycan, and sarcospan) by immunofluorescence (IF) and Western blot (WB), and performed electroretinography. Compared to the WT, Sgcd-/- mice are five times more likely to have retinal ruptures. Additionally, all the retinal layers are significantly thinner, more so in the inner plexiform layer (IPL). In addition, the number of nuclei in the KO versus the WT is ever so slightly increased. WT mice express Sgcd-protein partners in specific retinal layers, and as expected, KO mice have decreased or no protein expression, with a significant increase in the α subunit. At three months of age, there were no significant differences in the scotopic electroretinographic responses, regarding both a- and b-waves. According to our data, Sgcd-/- has a phenotype that is compatible with retinal degeneration.

WHOLE SEQUENCING OF THE MITOCHONDRIAL GENOME OF BREAST CANCER TISSUE IN MEXICAN-MESTIZO POSTMENOPAUSAL WOMEN WITH DIFFERENT BODY MASS INDEX.

BACKGROUND: Mitochondrial and oxidative stress has been related to obesity and breast cancer being this cancer more frequent and more aggressive in postmenopausal women with obesity. OBJECTIVE: The objective of this study was to investigate whether Mexican-Mestizo postmenopausal women with breast cancer and obesity present different somatic mutations in the mitochondrial DNA (mtDNA) when compared to women with normal body mass index (BMI). SUBJECTS AND METHODS: We included six Mexican-Mestizo postmenopausal women bearing breast cancer and who underwent mastectomy or breast-conserving surgery. BMI was determined in each case. Patients' genomic DNA was isolated from blood leukocytes and tumor tissue samples. Whole mtDNA sequence was determined by MitoChip v2.0 mitochondrial resequencing array, and data were analyzed using the GeneChip Sequence Analysis Software. Tumor mtDNA sequence was compared with matched leukocyte mtDNA sequence. RESULTS: Three women had a normal BMI and three presented obesity. Overall, we found 64 genetic variants: 53.1% were somatic mutations and 46.9% were polymorphisms; 44.1% were in the non-coding region and 55.9% were in genes that encode for mitochondrial proteins. Among the somatic mutations, 67.7% were in patients with normal BMI and 32.3% in patients with obesity. CONCLUSIONS: We did not find a higher frequency of mitochondrial somatic mutations in postmenopausal women with breast cancer and obesity compared to those with normal BMI. However, results could be due to the small number of women studied.

Whole sequencing of the mitochondrial genome of breast cancer tissue in Mexican-mestizo postmenopausal women with different body mass index

Abstract Background Mitochondrial and oxidative stress has been related to obesity and breast cancer being this cancer more frequent and more aggressive in postmenopausal women with obesity. Objective The objective of this study was to investigate whether Mexican-Mestizo postmenopausal women with breast cancer and obesity present different somatic mutations in the mitochondrial DNA (mtDNA) when compared to women with normal body mass index (BMI). Subjects and Methods We included six Mexican-Mestizo postmenopausal women bearing breast cancer and who underwent mastectomy or breast-conserving surgery. BMI was determined in each case. Patients’ genomic DNA was isolated from blood leukocytes and tumor tissue samples. Whole mtDNA sequence was determined by MitoChip v2.0 mitochondrial resequencing array, and data were analyzed using the GeneChip Sequence Analysis Software. Tumor mtDNA sequence was compared with matched leukocyte mtDNA sequence. Results Three women had a normal BMI and three presented obesity. Overall, we found 64 genetic variants: 53.1% were somatic mutations and 46.9% were polymorphisms; 44.1% were in the non-coding region and 55.9% were in genes that encode for mitochondrial proteins. Among the somatic mutations, 67.7% were in patients with normal BMI and 32.3% in patients with obesity. Conclusions We did not find a higher frequency of mitochondrial somatic mutations in postmenopausal women with breast cancer and obesity compared to those with normal BMI. However, results could be due to the small number of women studied.

Interleukin-27 polymorphisms are associated with premature coronary artery disease and metabolic parameters in the Mexican population: the genetics of atherosclerotic disease (GEA) Mexican study.

Several studies suggest an important role of Interleukin-27 in the development of atherosclerosis. The aim of this study was to establish whether the IL-27p28 gene polymorphisms are associated with premature coronary artery disease and/or other cardiovascular risk factors. Four IL-27p28 gene polymorphisms were selected and genotyped in 1162 premature coronary artery disease cases and 1107 controls. rs26528 T and rs40837 A alleles were significantly associated with a lower risk of premature coronary artery disease under different inheritance models (Pdominant = 0.046; Pover-dominant = 0.002; Pco-dominant1 = 0.007 for rs26528T; Pover-dominant = 0.008 and Pco-dominant1 = 0.031 for rs40837). The rs40837 A allele was also associated with a lower risk of insulin resistance, in cases (Pover-dominant = 0.037) and controls (Padditive = 0.008; Pdominant = 0.047; Precessive = 0.014; Pco-dominant2 = 0.006), while the rs26528 T allele was associated with a lower risk of insulin resistance only in the control group (Precessive = 0.016; Pco-dominant2 = 0.021). Interleukin-27 plasma levels were measured in 450 controls and 450 cases, and were significantly higher in cases compared to controls (P = 0.004). However, Interleukin-27 plasma levels were not associated with IL-27p28 polymorphisms. Luciferase assays showed that co-transfection of the rs40837 A allele and miR-379-5p significantly decreased luciferase gene expression. Our study shows for the first time, that IL-27p28 gene polymorphisms are associated with premature coronary artery disease and with some metabolic parameters. The rs40837 A allele in presence of miR-379-5p significantly decreased luciferase gene expression.

Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F.

BACKGROUND: Sarcospan (SSPN) is a transmembrane protein that interacts with the sarcoglycans (SGs) to form a tight subcomplex within the dystrophin-glycoprotein complex that spans the sarcolemma and interacts with laminin in the extracellular matrix. Overexpression of SSPN ameliorates Duchenne muscular dystrophy in murine models. METHODS: Standard cloning approaches were used to identify nanospan, and nanospan-specific polyclonal antibodies were generated and validated. Biochemical isolation of skeletal muscle membranes and two-photon laser scanning microscopy were used to analyze nanospan localization in muscle from multiple murine models. Duchenne muscular dystrophy biopsies were analyzed by immunoblot analysis of protein lysates as well as indirect immunofluorescence analysis of muscle cryosections. RESULTS: Nanospan is an alternatively spliced isoform of sarcospan. While SSPN has four transmembrane domains and is a core component of the sarcolemmal dystrophin-glycoprotein complex, nanospan is a type II transmembrane protein that does not associate with the dystrophin-glycoprotein complex. We demonstrate that nanospan is enriched in the sarcoplasmic reticulum (SR) fractions and is not present in the T-tubules. SR fractions contain membranes from three distinct structural regions: a region flanking the T-tubules (triadic SR), a SR region across the Z-line (ZSR), and a longitudinal SR region across the M-line (LSR). Analysis of isolated murine muscles reveals that nanospan is mostly associated with the ZSR and triadic SR, and only minimally with the LSR. Furthermore, nanospan is absent from the SR of δ-SG-null (Sgcd-/-) skeletal muscle, a murine model for limb girdle muscular dystrophy 2F. Analysis of skeletal muscle biopsies from Duchenne muscular dystrophy patients reveals that nanospan is preferentially expressed in type I (slow) fibers in both control and Duchenne samples. Furthermore, nanospan is significantly reduced in Duchenne biopsies. CONCLUSIONS: Alternative splicing of proteins from the SG-SSPN complex produces δ-SG3, microspan, and nanospan that localize to the ZSR and the triadic SR, where they may play a role in regulating resting calcium levels as supported by previous studies (Estrada et al., Biochem Biophys Res Commun 340:865-71, 2006). Thus, alternative splicing of SSPN mRNA generates three protein isoforms (SSPN, microspan, and nanospan) that differ in the number of transmembrane domains affecting subcellular membrane association into distinct protein complexes.

(-)-Epicatechin induces physiological cardiac growth by activation of the PI3K/Akt pathway in mice.

SCOPE: The flavanol (-)-epicatechin (Epi) has cardioprotective effects and improves physical capacity in normal mice. In addition, Epi increases nitric oxide (NO) production by activation of both PI3K/Akt or Ca2+ /CaMI/CaMKII (where Akt is protein kinase B; PI3K is phosphoinositide 3-kinase; CaMI is calmodulin; CaMKII is Ca2+ /calmodulin-dependent protein kinase II) signaling pathways, which have been associated with physiological and pathological cardiac hypertrophy, respectively. Notwithstanding all this information, few studies have been carried out that aimed to determine the potential beneficial effects that Epi may have in normal heart. METHODS AND RESULTS: Mice were treated by oral gavage with the flavanol Epi. The treatment induced a significant increase in heart weight, size of the free walls, and size of the cardiac fibers. Also, no evidence of cardiac fibrosis was revealed. Furthermore, the phosphorylation level of PI3K/Akt/mTOR/p70S6K (where mTOR is mammalian target of rapamycin; p70S6K is ribosomal protein S6 kinase beta-1) proteins was significantly higher in the heart of Epi-treated animals. In contrast, a significantly decreased level of pathological cardiac hypertrophy markers atrial natriuretic peptide and brain natriuretic peptide was observed along with no modification in the level of ß myosin heavy chain beta, calmodulin, and Ca2+ /calmodulin-dependent protein kinase II proteins. Hemodynamic parameters indicated an improvement in mechanical heart performance after Epi treatment. Interestingly, morphometric parameters were similar between treated and untreated mice after 4 wk without treatment. CONCLUSION: These findings indicate that Epi treatment induced physiological cardiac growth in healthy mice by activation of the PI3K/Akt pathway.

Functional Polymorphism rs13306560 of the MTHFR Gene Is Associated With Essential Hypertension in a Mexican-Mestizo Population.

BACKGROUND: Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have been associated with diastolic blood pressure, hypertension, and other cardiovascular diseases; however, results of these studies are still controversial. In this study, we sought to determine whether 2 functional variants (rs1801133 and rs13306560) within the MTHFR are associated with hypertension in Mexican-Mestizos. METHODS AND RESULTS: We performed a case-control study with 1214 subjects including adults and children to test for the association of both single nucleotide polymorphisms with essential hypertension. The adult group included 764 participants (372 patients and 391 controls) and the group of children included 418 participants (209 patients and 209 controls). rs13306560 was associated with essential hypertension in adults (odds ratio, 4.281; 95% confidence interval, 1.841-9.955; P=0.0003) with a statistical power >0.8. In children, none of the polymorphisms was associated with essential hypertension. In addition, we assessed the effect of the rs13306560 polymorphism on the MTHFR promoter region by means of luciferase reporter gene assays using human umbilical vein endothelial cells. Cells transfected with the pMTHFRaLUC construct showed an ≈25% reduction in luciferase activity (P=0.003). Furthermore, the promoter activity was reduced considerably by in vitro methylation of CpG sequences. CONCLUSIONS: Our data suggest that the rs13306560 polymorphism of the MTHFR may be part of the observed hypertension process in Mexican-Mestizo populations, but further studies are warranted. In addition, the allele A of the rs13306560 polymorphism as well as the in vitro methylation of CpGs reduced the promoter activity of the MTHFR regulatory region.

Molecular subtypification of human papillomavirus in male adult individuals with recurrent respiratory papillomatosis.

OBJECTIVE: This study aimed to identify the isotype of human papillomavirus (HPV) in fresh tissue samples of 35 male adults with adult recurrent adult respiratory papillomatosis which may be important to define the precise etiology of the disease, and determine the therapeutic and prophylactic measures. METHODS: A total of 35 adult male patients diagnosed with active RRP who have been treated for several years were included in the study. DNA of patients was extracted from fresh biological samples and analyzed by PCR and a Linear Array® HPV Genotyping system. RESULTS: Most cases (95%) corresponded to adult-onset of RRP. A questionnaire was applied to obtain demographic and clinical data. Using a PCR-based detection system all patients showed the presence of HPV; 80% were positive for HPV-6, 8% for HPV-11 and one for HPV-16. CONCLUSION: Most patients presented HPV-6 and consequently it was not feasible to correlate clinical and demographic characteristics with viral type. Besides, co-infections were not evident. This knowledge may be relevant to delineate therapeutic and preventive measures.

Reduction of no-reflow and reperfusion injury with the synthetic 17ß-aminoestrogen compound Prolame is associated with PI3K/Akt/eNOS signaling cascade.

A high proportion of primary percutaneous coronary interventions performed in the setting of acute myocardial infarction, concur with inadequate myocardial perfusion at the microvascular level. This phenomenon, known as "no-reflow" contributes to reperfusion injury, poor prognosis and to unfavorable clinical outcome. In this study, we evaluated the hypothesis that the synthetic 17ß-aminoestrogen Prolame, may confer cardioprotection and prevent against no-reflow. In an open-chest model of 30-min ischemia and 90-min reperfusion, male Wistar rats were randomly assigned to different groups: Control, Prolame, Prolame followed by the nitric oxide synthase inhibitor (L-NAME), and 17ß-estradiol. Areas of risk, infarct size and no-reflow were determined by planimetry with triphenyltetrazolium chloride and thioflavin-S stains. Structural damage of the vasculature was measured as capillary compression in clarified tissue after intra-atrial injection of Microfil. Hemodynamic function was obtained at the end of stabilization, ischemia and reperfusion; nitric oxide (NO·) content was determined indirectly using the Griess reaction. Activation of the eNOS signaling cascade was determined by western blot. Prolame reduced the infarcted area, decreased the zones of no-reflow and capillary compression by activating the PI3K/Akt/eNOS signaling pathway in correlation with NO· increase. Prolame also activated endothelial cells augmenting NO· production, which was inhibited by ICI182780 (a selective estrogen receptor down-regulator), supporting the notion that the cardioprotective effect of Prolame involves the preservation of endothelium through the activation of estrogen receptor downstream signaling. Our results provide evidence that Prolame has potential therapeutic application in patients with AMI, as it prevents from both vascular and cardiac tissue damage.

Identification of putative ortholog gene blocks involved in gestant and lactating mammary gland development: a rodent cross-species microarray transcriptomics approach.

The mammary gland (MG) undergoes functional and metabolic changes during the transition from pregnancy to lactation, possibly by regulation of conserved genes. The objective was to elucidate orthologous genes, chromosome clusters and putative conserved transcriptional modules during MG development. We analyzed expression of 22,000 transcripts using murine microarrays and RNA samples of MG from virgin, pregnant, and lactating rats by cross-species hybridization. We identified 521 transcripts differentially expressed; upregulated in early (78%) and midpregnancy (89%) and early lactation (64%), but downregulated in mid-lactation (61%). Putative orthologous genes were identified. We mapped the altered genes to orthologous chromosomal locations in human and mouse. Eighteen sets of conserved genes associated with key cellular functions were revealed and conserved transcription factor binding site search entailed possible coregulation among all eight block sets of genes. This study demonstrates that the use of heterologous array hybridization for screening of orthologous gene expression from rat revealed sets of conserved genes arranged in chromosomal order implicated in signaling pathways and functional ontology. Results demonstrate the utilization power of comparative genomics and prove the feasibility of using rodent microarrays to identification of putative coexpressed orthologous genes involved in the control of human mammary gland development.

[Diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy: experience and recommendations for Mexico. Administración del Patrimonio de la Beneficencia Pública. Asociación de Distrofia Muscular de Occidente]. / Diagnóstico y tratamiento con esteroides de pacientes con distrofia muscular de Duchenne: experiencia y recomendaciones para México.

Duchenne muscular dystrophy is a severe, debilitating and progressive disease that affects 1 in 3,500 live male births in the world. The diagnosis should be confirmed by genetic testing to identify the mutation in the DMD gene or muscle biopsy and immunostaining to demonstrate the absence of dystrophin. Although up to now continues to be an incurable disease, this does not mean it has no treatment. Treatment should be multidisciplinary, looking for the functionality of the patient and avoiding or correcting complications, mainly cardio-respiratory and skeletal. Many proposals have been evaluated and implemented with the aim of improving the quality of life for these patients. The long-term steroids have shown significant benefits, such as prolonging ambulation, reduce the need for spinal surgery, improve cardiorespiratory function and increase survival and the quality of life. This document presents the recommendations based on the experience of the working group and experts worldwide on the diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy.

TITLE: Diagnostico y tratamiento con esteroides de pacientes con distrofia muscular de Duchenne: experiencia y recomendaciones para Mexico.La distrofia muscular de Duchenne es una enfermedad grave, incapacitante y progresiva que afecta a 1 de cada 3.500 recien nacidos varones alrededor del mundo. El diagnostico debera confirmarse mediante pruebas geneticas para identificar la mutacion en el gen DMD, o bien por biopsia muscular e inmunotincion para demostrar la ausencia de distrofina. Aunque actualmente continua siendo una enfermedad incurable, no significa que no tenga tratamiento. Este debe ser multidisciplinario, buscando la funcionalidad del paciente y evitando o corrigiendo las complicaciones, principalmente cardiorrespiratorias y esqueleticas. Se han evaluado e implementado multiples propuestas con la finalidad de mejorar la calidad de vida en estos pacientes. Los esteroides a largo plazo han demostrado importantes beneficios para los pacientes, prolongan la deambulacion, reducen la necesidad de cirugia de columna, mejoran la funcion cardiorrespiratoria, y aumentan la supervivencia y la calidad de vida. En este documento se presentan las recomendaciones con base en la experiencia del grupo de trabajo y de los expertos de ambito mundial sobre el diagnostico y el tratamiento con esteroides para los pacientes con distrofia muscular de Duchenne.

Diagnóstico y tratamiento con esteroides de pacientes con distrofia muscular de Duchenne: experiencia y recomendaciones para México / Diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy: experience and recommendations for Mexico

La distrofia muscular de Duchenne es una enfermedad grave, incapacitante y progresiva que afecta a 1 de cada 3.500 recién nacidos varones alrededor del mundo. El diagnóstico deberá confirmarse mediante pruebas genéticas para identificar la mutación en el gen DMD, o bien por biopsia muscular e inmunotinción para demostrar la ausencia de distrofina. Aunque actualmente continúa siendo una enfermedad incurable, no significa que no tenga tratamiento. Éste debe ser multidisciplinario, buscando la funcionalidad del paciente y evitando o corrigiendo las complicaciones, principalmente cardiorrespiratorias y esqueléticas. Se han evaluado e implementado múltiples propuestas con la finalidad de mejorar la calidad de vida en estos pacientes. Los esteroides a largo plazo han demostrado importantes beneficios para los pacientes, prolongan la deambulación, reducen la necesidad de cirugía de columna, mejoran la función cardiorrespiratoria, y aumentan la supervivencia y la calidad de vida. En este documento se presentan las recomendaciones con base en la experiencia del grupo de trabajo y de los expertos de ámbito mundial sobre el diagnóstico y el tratamiento con esteroides para los pacientes con distrofia muscular de Duchenne (AU)

Duchenne muscular dystrophy is a severe, debilitating and progressive disease that affects 1 in 3,500 live male births in the world. The diagnosis should be confirmed by genetic testing to identify the mutation in the DMD gene or muscle biopsy and immunostaining to demonstrate the absence of dystrophin. Although up to now continues to be an incurable disease, this does not mean it has no treatment. Treatment should be multidisciplinary, looking for the functionality of the patient and avoiding or correcting complications, mainly cardio-respiratory and skeletal. Many proposals have been evaluated and implemented with the aim of improving the quality of life for these patients. The longterm steroids have shown significant benefits, such as prolonging ambulation, reduce the need for spinal surgery, improve cardiorespiratory function and increase survival and the quality of life. This document presents the recommendations based on the experience of the working group and experts worldwide on the diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy (AU)

JAG1 and COL1A1 polymorphisms and haplotypes in relation to bone mineral density variations in postmenopausal Mexican-Mestizo Women.

Osteoporosis is characterized by low bone mineral density (BMD). One of the most important factors that influence BMD is the genetic contribution. The collagen type 1 alpha 1 (COL1A1) and the JAGGED (JAG1) have been investigated in relation to BMD. The aim of this study was to investigate the possible association between two single-nucleotide polymorphisms (SNPs) of COL1A1, their haplotypes, and one SNP of JAG1 with BMD in postmenopausal Mexican-Mestizo women. Seven hundred and fifty unrelated postmenopausal women were included. Risk factors were recorded and BMD was measured in lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Two SNPs in COL1A1 (rs1800012 and rs1107946) and one in JAG1 (rs2273061) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Deviations from Hardy-Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r (2), and haplotype analysis of COL1A1 was conducted. Under a dominant model, the rs1800012 polymorphism of the COL1A1 showed an association with BMD of the lumbar spine (P = 0.021). In addition, analysis of the haplotype of COL1A1 showed that the G-G haplotype presented a higher BMD in lumbar spine. We did not find an association between the s1107946 and rs2273061 polymorphisms of the COL1A1 and JAG1, respectively. Our results suggest that the rs1800012 polymorphism of the COL1A1, in addition to one haplotype, were significantly associated with BMD variation in Mexican-Mestizo postmenopausal women.

Immunodetection analysis of muscular dystrophies in Mexico.

INTRODUCTION: The muscular dystrophies (MDs) result from perturbations in the myofibers. These alterations are induced in part by mechanical stress due to membrane cell fragility, disturbances in mechanotransduction pathways, muscle cell physiology, and metabolism. METHODS: We analyzed 290 biopsies of patients with a clinical diagnosis of muscular dystrophy. Using immunofluorescence staining, we searched for primary and secondary deficiencies of 12 different proteins, including membrane, costamere, cytoskeletal, and nuclear proteins. In addition, we analyzed calpain-3 by immunoblot. RESULTS: We identified 212 patients with varying degrees of protein deficiencies, including dystrophin, sarcoglycans, dysferlin, caveolin-3, calpain-3, emerin, and merosin. Moreover, 78 biopsies showed normal expression of all investigated muscle proteins. The frequency rates of protein deficiencies were as follows: 52.36% dystrophinopathies; 18.40% dysferlinopathies; 14.15% sarcoglycanopathies; 11.32% calpainopathies; 1.89% merosinopathies; 1.42% caveolinopathies; and 0.47% emerinopathies. Deficiencies in lamin A/C and telethonin were not detected. CONCLUSION: We have described the frequency of common muscular dystrophies in Mexico.

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

Introducción. La distrofia muscular de Duchenne (DMD) es un trastorno caracterizado por atrofia muscular progresiva y debilidad, debido a la ausencia o alteración de la función de la distrofina, una proteína que protege a las células del músculo de la tensión mecánica inducida durante la contracción. Las mutaciones en el gen DMD pueden dar lugar a diferentes fenotipos clínicos, conocidos colectivamente como distrofinopatías, de los cuales la DMD es el más grave. Caso clínico. Se presenta una deleción nueva de los exones 24-41, que no interrumpe el marco de lectura y se espera que origine un fenotipo leve. Por el contrario, el paciente tiene un fenotipo DMD grave. Conclusiones. Nuestra comunicación apoya la hipótesis de que la interrupción del sitio de unión a gamma-actina situado en el dominio cilíndrico central desempeña un papel crucial en la función de amortiguador de distrofina en las células musculares. La descripción de las variantes patogénicas en el gen DMD y los fenotipos resultantes tienen importantes implicaciones en el diseño de estrategias terapéuticas moleculares para la DMD (AU)

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 (AU)

[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.