Myopia has reached epidemic proportions in the world, especially in East Asia. Pathologic myopia is an extreme type of high myopia that can cause irreversible blindness. Myopic maculopathy is one of the characteristics of pathologic myopia. Nowadays, limited treatments can preserve the visual outcome of these patients. We review the current treatment in practice for myopic maculopathy. Furthermore, based on the current stem cell-based therapy used in degenerative ocular diseases, we discuss a new concept of stem cell therapy for myopic maculopathy.
{"title":"Stem cell-based therapy for myopic maculopathy: a new concept","authors":"Ya Ma, Yan-Ping Li, Zi-Bing Jin","doi":"10.20517/jtgg.2021.48","DOIUrl":"https://doi.org/10.20517/jtgg.2021.48","url":null,"abstract":"Myopia has reached epidemic proportions in the world, especially in East Asia. Pathologic myopia is an extreme type of high myopia that can cause irreversible blindness. Myopic maculopathy is one of the characteristics of pathologic myopia. Nowadays, limited treatments can preserve the visual outcome of these patients. We review the current treatment in practice for myopic maculopathy. Furthermore, based on the current stem cell-based therapy used in degenerative ocular diseases, we discuss a new concept of stem cell therapy for myopic maculopathy.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F. Ghaseminejad, B. Tam, Colette N. Chiu, J. Feehan, O. L. Moritz
Aim: To examine the utility of gene editing therapies for retinitis pigmentosa using Xenopus laevis carrying a mutation in Rhodopsin. Methods: Xenopus laevis were genetically modified using CRISPR-Cas9 based methods and characterized by Sanger sequencing, dot blot, electroretinography, and confocal microscopy. Results: We identified genetically modified Xenopus laevis carrying a net 12 base pair deletion in the Rho.L gene. These animals have a retinal degeneration that is apparent by 14 days, with abnormal or missing rod outer segments, and a reduced electroretinogram signal. We prevented the majority of this retinal degeneration via a treatment strategy using a single sgRNA to neutralize the mutant allele via non-homologous end joining, yielding long-term improvements in histology and the electroretinogram. A second strategy using two sgRNAs to generate large deletions in the mutant allele was also successful, but did not significantly improve outcomes relative to the single-guide strategy as it was less efficient. We found limited evidence of success with a third strategy dependent on homology-directed repair; this treatment was also too inefficient to generate an outcome superior to the single-guide strategy. Conclusion: Our results demonstrate the utility of this new Xenopus laevis model for rapidly assessing and comparing multiple gene-editing based treatment strategies. We conclude that it would be technically difficult to improve on the simple single-guide based strategy, as strategies requiring multiple successive events (such as cleavage followed by homology-directed repair) are likely to be less efficient.
{"title":"Gene editing treatment strategies for retinitis pigmentosa assessed in Xenopus laevis carrying a mutant Rhodopsin allele","authors":"F. Ghaseminejad, B. Tam, Colette N. Chiu, J. Feehan, O. L. Moritz","doi":"10.20517/jtgg.2021.49","DOIUrl":"https://doi.org/10.20517/jtgg.2021.49","url":null,"abstract":"Aim: To examine the utility of gene editing therapies for retinitis pigmentosa using Xenopus laevis carrying a mutation in Rhodopsin. Methods: Xenopus laevis were genetically modified using CRISPR-Cas9 based methods and characterized by Sanger sequencing, dot blot, electroretinography, and confocal microscopy. Results: We identified genetically modified Xenopus laevis carrying a net 12 base pair deletion in the Rho.L gene. These animals have a retinal degeneration that is apparent by 14 days, with abnormal or missing rod outer segments, and a reduced electroretinogram signal. We prevented the majority of this retinal degeneration via a treatment strategy using a single sgRNA to neutralize the mutant allele via non-homologous end joining, yielding long-term improvements in histology and the electroretinogram. A second strategy using two sgRNAs to generate large deletions in the mutant allele was also successful, but did not significantly improve outcomes relative to the single-guide strategy as it was less efficient. We found limited evidence of success with a third strategy dependent on homology-directed repair; this treatment was also too inefficient to generate an outcome superior to the single-guide strategy. Conclusion: Our results demonstrate the utility of this new Xenopus laevis model for rapidly assessing and comparing multiple gene-editing based treatment strategies. We conclude that it would be technically difficult to improve on the simple single-guide based strategy, as strategies requiring multiple successive events (such as cleavage followed by homology-directed repair) are likely to be less efficient.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Karolina Plössl, E. Webster, C. Kiel, F. Grassmann, C. Brandl, B. Weber
Aim: To model a complex retinal disease such as age-related macular degeneration (AMD) in vitro, we aimed to combine genetic and environmental risk factors in a retinal pigment epithelium (RPE) cell culture model generated via induced pluripotent stem cells (iPSCs) from subjects with an extremely high and an extremely low genetic disease risk. As an external stimulus, we chose defined oxidative stress conditions. Methods: Patients were genotyped for known AMD-associated genetic variants and their individual genetic risk score (GRS) was calculated defining individual iPSC-RPE cell lines which reflect the extreme ends of the genetic risk for AMD. Sodium iodate (NaIO3, SI) was used to induce oxidative stress and cellular responses were followed by analyzing nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation by mRNA and protein expression. Results: We present a collection of eight iPSC-RPE cell lines, with four each harboring an extreme low or an extreme high GRS for AMD. RPE identity was verified structurally and functionally. We found that 24 and 72 h of SI treatment induced a significant upregulation of NRF2 response genes HMOX1 and NQO1, without showing cytotoxic effects or negatively influencing RPE cell integrity. High- vs. low-risk cell lines revealed similar first line defenses in oxidative stress response mediated through the NRF2 pathway. Conclusion: Delineating the NRF2-mediated oxidative stress response was sought in iPSC-RPE cell lines with maximally divergent genetic AMD risk profiles. Under the specific stress conditions chosen, our data indicate that genetic predisposition to AMD may not exert a major influence on the NRF2 signaling pathway.
{"title":"In vitro modeling of the complex retinal condition age-related macular degeneration","authors":"Karolina Plössl, E. Webster, C. Kiel, F. Grassmann, C. Brandl, B. Weber","doi":"10.20517/jtgg.2021.39","DOIUrl":"https://doi.org/10.20517/jtgg.2021.39","url":null,"abstract":"Aim: To model a complex retinal disease such as age-related macular degeneration (AMD) in vitro, we aimed to combine genetic and environmental risk factors in a retinal pigment epithelium (RPE) cell culture model generated via induced pluripotent stem cells (iPSCs) from subjects with an extremely high and an extremely low genetic disease risk. As an external stimulus, we chose defined oxidative stress conditions. Methods: Patients were genotyped for known AMD-associated genetic variants and their individual genetic risk score (GRS) was calculated defining individual iPSC-RPE cell lines which reflect the extreme ends of the genetic risk for AMD. Sodium iodate (NaIO3, SI) was used to induce oxidative stress and cellular responses were followed by analyzing nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation by mRNA and protein expression. Results: We present a collection of eight iPSC-RPE cell lines, with four each harboring an extreme low or an extreme high GRS for AMD. RPE identity was verified structurally and functionally. We found that 24 and 72 h of SI treatment induced a significant upregulation of NRF2 response genes HMOX1 and NQO1, without showing cytotoxic effects or negatively influencing RPE cell integrity. High- vs. low-risk cell lines revealed similar first line defenses in oxidative stress response mediated through the NRF2 pathway. Conclusion: Delineating the NRF2-mediated oxidative stress response was sought in iPSC-RPE cell lines with maximally divergent genetic AMD risk profiles. Under the specific stress conditions chosen, our data indicate that genetic predisposition to AMD may not exert a major influence on the NRF2 signaling pathway.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genes have long been considered to cause autism spectrum disorder (ASD). However, data obtained over the last 10 years indicate that the true role of genetics in ASD and the cost-benefit ratio of genetic testing following an ASD diagnosis warrant further investigation. ASD is heterogeneous with high individual complexity, and new findings related to systemic alterations in ASD (in addition to genetics) should be considered when attempting to optimize patient health. However, for some people with ASD and their families, genetic testing can identify genetic mutations or chromosomic alterations. This review mainly considers recent research (the last 5 years) on the role of genetic factors in ASD and the importance of genetic testing in a new Advanced Integrative Model of ASD.
{"title":"The importance of genetics in an advanced integrative model of autism spectrum disorder","authors":"Andrés Ciolino, M. Ferreira, Nicolás Loyacono","doi":"10.20517/jtgg.2022.15","DOIUrl":"https://doi.org/10.20517/jtgg.2022.15","url":null,"abstract":"Genes have long been considered to cause autism spectrum disorder (ASD). However, data obtained over the last 10 years indicate that the true role of genetics in ASD and the cost-benefit ratio of genetic testing following an ASD diagnosis warrant further investigation. ASD is heterogeneous with high individual complexity, and new findings related to systemic alterations in ASD (in addition to genetics) should be considered when attempting to optimize patient health. However, for some people with ASD and their families, genetic testing can identify genetic mutations or chromosomic alterations. This review mainly considers recent research (the last 5 years) on the role of genetic factors in ASD and the importance of genetic testing in a new Advanced Integrative Model of ASD.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67659018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In this review we present contemporary understanding of aetiological heterogeneity in Hodgkin lymphoma, discuss how this may influence tumour phenotype and whether it does or may impact treatment outcomes. Many new treatments are being tested in this era. We especially discuss T-cell therapy and immune checkpoint blockade, because these two modern treatments are expected to have differential efficacy by the presence/absence of Epstein-Barr virus in the malignant Hodgkin-Reed-Sternberg cells. Survival after Hodgkin lymphoma is excellent in many patient strata with first-line treatment, but less so for patients with refractory or relapsing disease. On the other hand, this good prognosis also means that very large trials are needed to demonstrate superior efficacy of new treatment regimes. And our understanding of aetiological heterogeneity in Hodgkin lymphoma and how it affects prognosis is hampered for the same reason. We discuss the potential for fine-tuning risk stratification and treatment based on information that is little used today.
{"title":"Clinical significance of aetiological heterogeneity in classical Hodgkin lymphoma","authors":"H. Hjalgrim, K. Rostgaard","doi":"10.20517/jtgg.2021.46","DOIUrl":"https://doi.org/10.20517/jtgg.2021.46","url":null,"abstract":"In this review we present contemporary understanding of aetiological heterogeneity in Hodgkin lymphoma, discuss how this may influence tumour phenotype and whether it does or may impact treatment outcomes. Many new treatments are being tested in this era. We especially discuss T-cell therapy and immune checkpoint blockade, because these two modern treatments are expected to have differential efficacy by the presence/absence of Epstein-Barr virus in the malignant Hodgkin-Reed-Sternberg cells. Survival after Hodgkin lymphoma is excellent in many patient strata with first-line treatment, but less so for patients with refractory or relapsing disease. On the other hand, this good prognosis also means that very large trials are needed to demonstrate superior efficacy of new treatment regimes. And our understanding of aetiological heterogeneity in Hodgkin lymphoma and how it affects prognosis is hampered for the same reason. We discuss the potential for fine-tuning risk stratification and treatment based on information that is little used today.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carolina Puyana, Emma Schindler, Eunkyung Lee, Jennifer J. Hu
Aim: Multiple genes and genetic variants may contribute to racial/ethnic disparities in obesity-associated breast cancer diagnosis and prognosis. Therefore, we evaluate whether racial/ethnic differences in polygenic risk score (PRS) contribute to obesity and inflammatory biomarker in breast cancer patients. Methods: In a tri-racial/ethnic population of 403 breast cancer patients, 21% African American (AA), 65% Hispanic White (HW), and 14% non-Hispanic White (NHW), we evaluated racial/ethnic differences in obesity PRS, the association between PRS and an inflammatory biomarker C-reactive protein (CRP), and its implication in bariatric surgery eligibility. The obesity PRS was constructed via a weighted risk allele model using 35 obesity-related single nucleotide polymorphisms (SNPs). SAS version 9.3 for Windows (SAS Institute, Cary, NC, USA) was used to perform the logistic regression analysis. Results: About 74% of our study population were overweight or obese. The mean ± SD of obesity PRS was 45.03 ± 10.66 for obese patients and 39.36 ± 8.81 for non-obese patients (P < 0.0001). AA patients had a significantly higher obesity PRS than HW and NHW (P < 0.0001). The obesity PRS significantly correlated with body mass index and CRP levels (P < 0.0001) and was associated with bariatric surgery eligibility (OR = 4.32, 95%CI: 1.89-9.87). Conclusion: In summary, multiple obesity-associated SNPs contribute to racial/ethnic disparities in obesity of breast cancer patients; the obesity PRS has application in identifying breast cancer patients with higher genetic risk for obesity who may benefit from more aggressive weight management, such as bariatric surgery to improve breast cancer clinical outcomes.
目的:多基因和遗传变异可能导致肥胖相关乳腺癌诊断和预后的种族差异。因此，我们评估多基因风险评分(PRS)的种族/民族差异是否有助于乳腺癌患者的肥胖和炎症生物标志物。方法:在403名三种族/民族乳腺癌患者中，21%的非裔美国人(AA)， 65%的西班牙裔白人(HW)和14%的非西班牙裔白人(NHW)，我们评估了肥胖PRS的种族/民族差异，PRS与炎症生物标志物c反应蛋白(CRP)之间的关系，及其对减肥手术资格的影响。利用35个肥胖相关单核苷酸多态性(snp)，通过加权风险等位基因模型构建肥胖PRS。采用SAS version 9.3 for Windows (SAS Institute, Cary, NC, USA)进行logistic回归分析。结果:约74%的研究人群超重或肥胖。肥胖患者的平均±SD为45.03±10.66，非肥胖患者的平均±SD为39.36±8.81 (P < 0.0001)。AA患者的肥胖PRS显著高于HW和NHW (P < 0.0001)。肥胖PRS与体重指数和CRP水平显著相关(P < 0.0001)，并与减肥手术资格相关(OR = 4.32, 95%CI: 1.89-9.87)。结论:综上所述，多个肥胖相关snp导致了乳腺癌患者肥胖的种族差异;肥胖PRS应用于识别具有较高肥胖遗传风险的乳腺癌患者，这些患者可能受益于更积极的体重管理，如减肥手术以改善乳腺癌的临床结果。
{"title":"Genetic predisposition to obesity and inflammation in a tri-racial/ethnic breast cancer population","authors":"Carolina Puyana, Emma Schindler, Eunkyung Lee, Jennifer J. Hu","doi":"10.20517/jtgg.2021.51","DOIUrl":"https://doi.org/10.20517/jtgg.2021.51","url":null,"abstract":"Aim: Multiple genes and genetic variants may contribute to racial/ethnic disparities in obesity-associated breast cancer diagnosis and prognosis. Therefore, we evaluate whether racial/ethnic differences in polygenic risk score (PRS) contribute to obesity and inflammatory biomarker in breast cancer patients. Methods: In a tri-racial/ethnic population of 403 breast cancer patients, 21% African American (AA), 65% Hispanic White (HW), and 14% non-Hispanic White (NHW), we evaluated racial/ethnic differences in obesity PRS, the association between PRS and an inflammatory biomarker C-reactive protein (CRP), and its implication in bariatric surgery eligibility. The obesity PRS was constructed via a weighted risk allele model using 35 obesity-related single nucleotide polymorphisms (SNPs). SAS version 9.3 for Windows (SAS Institute, Cary, NC, USA) was used to perform the logistic regression analysis. Results: About 74% of our study population were overweight or obese. The mean ± SD of obesity PRS was 45.03 ± 10.66 for obese patients and 39.36 ± 8.81 for non-obese patients (P < 0.0001). AA patients had a significantly higher obesity PRS than HW and NHW (P < 0.0001). The obesity PRS significantly correlated with body mass index and CRP levels (P < 0.0001) and was associated with bariatric surgery eligibility (OR = 4.32, 95%CI: 1.89-9.87). Conclusion: In summary, multiple obesity-associated SNPs contribute to racial/ethnic disparities in obesity of breast cancer patients; the obesity PRS has application in identifying breast cancer patients with higher genetic risk for obesity who may benefit from more aggressive weight management, such as bariatric surgery to improve breast cancer clinical outcomes.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
D. Casas-Alba, J. Hoenicka, Alba Vilanova-Adell, L. Vega-Hanna, J. Pijuan, F. Palau
Abstract Rare diseases are life-threatening or chronically debilitating conditions affecting millions of people worldwide. In many instances, the patients experience a delay in their diagnosis or remain undiagnosed despite extensive investigations carried out by specialists. There are several explanations to account for this phenomenon including the socioeconomic context and the lack of an established consensus for diagnostic testing. Nonetheless, the widespread use of genetic and genomic tests in the past decades has had a major impact on clinical reasoning paradigms, and new troves of data are constantly being generated and analyzed. This requires constantly updating tools to match the discovery rate and allow reanalysis. In this review, we summarize the latest international recommendations and guidelines to address the problem of diagnostic deficit as well as present the current diagnostic workflows. Increasing access to exome and genome sequencing technologies and biological validation, gaining insight into the interpretation of multi-omics datasets, and fostering data sharing would reduce the long diagnostic odyssey and diagnostic gap.
{"title":"Diagnostic strategies in patients with undiagnosed and rare diseases","authors":"D. Casas-Alba, J. Hoenicka, Alba Vilanova-Adell, L. Vega-Hanna, J. Pijuan, F. Palau","doi":"10.20517/jtgg.2022.03","DOIUrl":"https://doi.org/10.20517/jtgg.2022.03","url":null,"abstract":"Abstract Rare diseases are life-threatening or chronically debilitating conditions affecting millions of people worldwide. In many instances, the patients experience a delay in their diagnosis or remain undiagnosed despite extensive investigations carried out by specialists. There are several explanations to account for this phenomenon including the socioeconomic context and the lack of an established consensus for diagnostic testing. Nonetheless, the widespread use of genetic and genomic tests in the past decades has had a major impact on clinical reasoning paradigms, and new troves of data are constantly being generated and analyzed. This requires constantly updating tools to match the discovery rate and allow reanalysis. In this review, we summarize the latest international recommendations and guidelines to address the problem of diagnostic deficit as well as present the current diagnostic workflows. Increasing access to exome and genome sequencing technologies and biological validation, gaining insight into the interpretation of multi-omics datasets, and fostering data sharing would reduce the long diagnostic odyssey and diagnostic gap.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Estévez-Arias, L. Carrera-García, A. Nascimento, L. Cantarero, J. Hoenicka, F. Palau
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting at least 1 in 2500 individuals. CMT refers to a heterogeneous group of inherited neuropathies from both phenotypic and genetic points of view. Over the last decades, there have been important advances not only in the identification of causative genes but also in understanding the molecular basis for many forms of CMT. In fact, to date, around 100 genes have been related to CMT disease, thanks to next generation sequencing techniques, and they have been proven to affect either the myelin or axon of peripheral nerves. Moreover, its genetic diagnosis has remarkedly improved, although there are still difficulties when it comes to treatment. In this review, we explore in depth the eight most prevalent genes associated with CMT: GDAP1, GJB1, HINT1, MFN2, MPZ, PMP22, SH3TC2, and SORD. We also address the disrupted cellular processes and pathophysiological mechanisms involved in the disease. A better understanding of the pathogenic mechanisms responsible for each type of CMT would be essential to identifying molecular targets and therapeutic strategies.
{"title":"Genetic approaches and pathogenic pathways in the clinical management of Charcot-Marie-Tooth disease","authors":"B. Estévez-Arias, L. Carrera-García, A. Nascimento, L. Cantarero, J. Hoenicka, F. Palau","doi":"10.20517/jtgg.2022.04","DOIUrl":"https://doi.org/10.20517/jtgg.2022.04","url":null,"abstract":"Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting at least 1 in 2500 individuals. CMT refers to a heterogeneous group of inherited neuropathies from both phenotypic and genetic points of view. Over the last decades, there have been important advances not only in the identification of causative genes but also in understanding the molecular basis for many forms of CMT. In fact, to date, around 100 genes have been related to CMT disease, thanks to next generation sequencing techniques, and they have been proven to affect either the myelin or axon of peripheral nerves. Moreover, its genetic diagnosis has remarkedly improved, although there are still difficulties when it comes to treatment. In this review, we explore in depth the eight most prevalent genes associated with CMT: GDAP1, GJB1, HINT1, MFN2, MPZ, PMP22, SH3TC2, and SORD. We also address the disrupted cellular processes and pathophysiological mechanisms involved in the disease. A better understanding of the pathogenic mechanisms responsible for each type of CMT would be essential to identifying molecular targets and therapeutic strategies.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Coronary artery disease (CAD) is a pandemic disease and the number one cause of death in the world. Predisposition to CAD is about 50% acquired and 50% genetic. CAD prevention has been proven in randomized clinical trials with statin therapy. However, primary prevention is limited by the lack of biomarkers to detect asymptomatic young individuals at risk. Traditional risk factors (TRFs) such as hypertension or Type 2 Diabetes are age-dependent and often not present until the sixth or seventh decade. In contrast, genetic risk determined at conception is potentially a biomarker to detect young individuals at risk for CAD. The first genetic risk variant for CAD (9p21) was discovered in 2007, and subsequently, over 200 risk variants for CAD were discovered. A genetic risk score (GRS) based on the genetic risk variants for CAD was evaluated in over one million individuals. Retrospective analysis of clinical trials assessing the effect of statin therapy showed that individuals with the highest GRS had the highest risk for cardiac events and also the most benefit from lowering cholesterol. In a recent study of 55,685 individuals, those with the highest GRS (20%) had a 91% higher risk for cardiac events. Furthermore, those with high genetic risk on a favorable lifestyle had 46% fewer cardiac events than those with an unfavorable lifestyle. The GRS is superior and independent of TRFs. Incorporation into clinical practice will be a paradigm shift in preventing this pandemic.
{"title":"Genetic risk and its role in primary prevention of CAD","authors":"R. Roberts, Judith Chavira, E. Venner","doi":"10.20517/jtgg.2022.07","DOIUrl":"https://doi.org/10.20517/jtgg.2022.07","url":null,"abstract":"Coronary artery disease (CAD) is a pandemic disease and the number one cause of death in the world. Predisposition to CAD is about 50% acquired and 50% genetic. CAD prevention has been proven in randomized clinical trials with statin therapy. However, primary prevention is limited by the lack of biomarkers to detect asymptomatic young individuals at risk. Traditional risk factors (TRFs) such as hypertension or Type 2 Diabetes are age-dependent and often not present until the sixth or seventh decade. In contrast, genetic risk determined at conception is potentially a biomarker to detect young individuals at risk for CAD. The first genetic risk variant for CAD (9p21) was discovered in 2007, and subsequently, over 200 risk variants for CAD were discovered. A genetic risk score (GRS) based on the genetic risk variants for CAD was evaluated in over one million individuals. Retrospective analysis of clinical trials assessing the effect of statin therapy showed that individuals with the highest GRS had the highest risk for cardiac events and also the most benefit from lowering cholesterol. In a recent study of 55,685 individuals, those with the highest GRS (20%) had a 91% higher risk for cardiac events. Furthermore, those with high genetic risk on a favorable lifestyle had 46% fewer cardiac events than those with an unfavorable lifestyle. The GRS is superior and independent of TRFs. Incorporation into clinical practice will be a paradigm shift in preventing this pandemic.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diana Garro-Núñez, Pablo Mora-Cubillo, Sammy Fonseca-Bone, María Jesús Picado-Martínez, Michael Fonseca-Brenes, Henriette Raventós-Vorst, Gabriela Chavarría-Soley
PM20D1 is a little studied enzyme until recently, belonging to the mammalian M20 peptidase family, which catalyzes both the synthesis and hydrolysis of N-acyl amino acids (NAAs). NAAs are bioactive lipids biosynthesized from free fatty acids and free amino acids. These molecules have been associated with many biological functions; however, most of the biochemical mechanisms have not yet been described. The best-known biochemical mechanism is the one involved in thermogenesis, which also has implications for reactive oxygen species levels and cell preservation. In the last few years, genetic variation in PM20D1, as well as changes in its methylation and expression levels, have been reported to be associated with several disease phenotypes, including Alzheimer’s disease. In this review, we explore the current knowledge regarding the PM20D1 gene, including aspects such as its biology, potential functions, regulation of its expression, and role in different phenotypes such as Alzheimer’s disease, obesity, Parkinson’s disease, and several other disorders.
{"title":"The many roles of the Alzheimer-associated gene PM20D1","authors":"Diana Garro-Núñez, Pablo Mora-Cubillo, Sammy Fonseca-Bone, María Jesús Picado-Martínez, Michael Fonseca-Brenes, Henriette Raventós-Vorst, Gabriela Chavarría-Soley","doi":"10.20517/jtgg.2022.10","DOIUrl":"https://doi.org/10.20517/jtgg.2022.10","url":null,"abstract":"PM20D1 is a little studied enzyme until recently, belonging to the mammalian M20 peptidase family, which catalyzes both the synthesis and hydrolysis of N-acyl amino acids (NAAs). NAAs are bioactive lipids biosynthesized from free fatty acids and free amino acids. These molecules have been associated with many biological functions; however, most of the biochemical mechanisms have not yet been described. The best-known biochemical mechanism is the one involved in thermogenesis, which also has implications for reactive oxygen species levels and cell preservation. In the last few years, genetic variation in PM20D1, as well as changes in its methylation and expression levels, have been reported to be associated with several disease phenotypes, including Alzheimer’s disease. In this review, we explore the current knowledge regarding the PM20D1 gene, including aspects such as its biology, potential functions, regulation of its expression, and role in different phenotypes such as Alzheimer’s disease, obesity, Parkinson’s disease, and several other disorders.","PeriodicalId":73999,"journal":{"name":"Journal of translational genetics and genomics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67658868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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