The Current Status of Genes and Genetic Testing in Emergency Medicine: A Narrative Review

Context: An emergency is any medical problem that could cause death or permanent injury if not treated quickly. In some occasions, the kind of urgent intervention depends on patient’s exact genetic background. Unfortunately, the importance of genes in medical emergencies has been forgotten in recent decades. Evidence acquisition: In order to find relevant articles, we searched two databases of Pubmed and Embase. The exact words of “genes”, “genetics”, “epigenetics”, “DNA”, and “emergency” were used alone and in combination. All studies like randomized clinical trials (RCT), case/controls, case series, case reports, and review articles were studied to find the related data. No time limitation was considered for the studies. Results: Several aspects of genetic testing are newly considered in emergency departments including cell-free DNA (cfDNA) for disease diagnosis, pharmacogenetics for decreasing the adverse drug effects, and personalized medicine for exact emergency interventions in diseases like Vascular Ehlers-Danlos syndrome (vEDS). Data from genetic testing and genome wide association studies have yielded promising results to make medical emergency interventions more beneficial in the near future. Conclusion: Taking everything into consideration, several advanced genetic and epigenetic alteration technologies can change emergency medicine for the better. Personalized genetic data of patients can turn emergency medicine to personalized medicine

The Current Status of Genes and Genetic Testing in Emergency Medicine: A Narrative Review

Context: An emergency is any medical problem that could cause death or permanent injury if not treated quickly. In some occasions, the kind of urgent intervention depends on patient’s exact genetic background. Unfortunately, the importance of genes in medical emergencies has been forgotten in recent decades. Evidence acquisition: In order to find relevant articles, we searched two databases of Pubmed and Embase. The exact words of “genes”, “genetics”, “epigenetics”, “DNA”, and “emergency” were used alone and in combination. All studies like randomized clinical trials (RCT), case/controls, case series, case reports, and review articles were studied to find the related data. No time limitation was considered for the studies. Results: Several aspects of genetic testing are newly considered in emergency departments including cell-free DNA (cfDNA) for disease diagnosis, pharmacogenetics for decreasing the adverse drug effects, and personalized medicine for exact emergency interventions in diseases like Vascular Ehlers-Danlos syndrome (vEDS). Data from genetic testing and genome wide association studies have yielded promising results to make medical emergency interventions more beneficial in the near future. Conclusion: Taking everything into consideration, several advanced genetic and epigenetic alteration technologies can change emergency medicine for the better. Personalized genetic data of patients can turn emergency medicine to personalized medicine

The POLG Polyglutamine Tract Variants in Iranian Patients with Multiple Sclerosis

How to Cite This Article: Khatami M, Heidari MM, Mansouri R, Mousavi F. The POLG Polyglutamine Tract Variants in Iranian Patients with Multiple Sclerosis. Iran J Child Neurol. 2015 Winter; 9(1):37-41.AbstractObjectiveMultiple Sclerosis (MS) is a common disease of the central nervous system. The interaction between inflammatory and neurodegenerative processes typically results in irregular neurological disturbances followed by progressive disability.Mitochondrial dysfunction has been implicated in neurodegenerative disorders. The DNA polymerase-gamma (POLG) gene, which encodes the catalytic subunit of enzyme responsible for directing mtDNA replication, contains a poly glutamine tract (poly-Q) in the N-terminal, encoded by a CAG sequence in exon 2.Materials & MethodsWe analyzed the POLG trinucleotide repeats in 40 Iranian patients with MS (27 females and 13 males with an age range of 18–55); and 47 healthy age, gender, and ethnic matched controls were chosen by PCR-SSCP analysis. ResultsOur results indicated that the most common allele in patients had 10 consecutive CAG repeats (10Q). Other alleles of 11and 12 trinucleotide repeats were detected.We did not find any difference between the CAG repeat length distribution in controls and MS patients.ConclusionNo correlation was observed in the POLG gene CAG repeat with pathogenesis of MS, but it looks that other point mutations in POLG gene may have an important role in the disease’s pathogenesis and produced more significant results.ReferencesBaranzini SE. Revealing the genetic basis of multiple sclerosis: are we there yet? Curr Opin Genet Dev. 2011 Jun; 21(3):317-24.Hoffjan S, Akkad DA. The genetics of multiple sclerosis: an update 2010. Mol Cell Probes. 2010 Oct; 24(5):237-43.Disanto G, Berlanga AJ, Handel AE, Para AE, Burrell AM, Fries A, et al. Heterogeneity in multiple sclerosis: scratching the surface of a complex disease. Autoimmune Dis. 2010; 2011:932351.International Multiple Sclerosis Genetics C, Wellcome Trust Case Control C, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 Aug 11; 476(7359):214-9.Mao P, Reddy PH. Is multiple sclerosis a mitochondrial disease? Biochimica et biophysica acta. 2010 Jan; 1802(1):66-79.Inarrea P, Alarcia R, Alava MA, Capablo JL, Casanova A, Iniguez C, et al. Mitochondrial complex enzyme activities and cytochrome C expression changes in multiple sclerosis. Mol Neurobiol. 2014 Feb; 49(1):1-9.Schaller A, Hahn D, Jackson CB, Kern I, Chardot C, Belli DC, et al. Molecular and biochemical characterization of a novel mutation in POLG associated with Alpers syndrome. BMC Neurology. 2011; 11(1):4.Milone M, Brunetti-Pierri N, Tang LY, Kumar N, Mezei MM, Josephs K, et al. Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. Neuromuscul Disord. 2008 Aug; 18(8):626-32.Azrak S, Ayyasamy V, Zirpoli G, Ambrosone C, Bandera EV, Bovbjerg DH, et al. CAG repeat variants in the POLG1 gene encoding mtDNA polymerase-gamma and risk of breast cancer in African-American women. PLoS One. 2012; 7(1):e29548.Eerola J, Luoma PT, Peuralinna T, Scholz S, Paisan-Ruiz C, Suomalainen A, et al. POLG1 polyglutamine tract variants associated with Parkinson’s disease. Neurosci Lett. 2010 Jun 14; 477(1):1-5.Rovio A, Abel J, Ahola A, Andres A, Bertranpetit J, Blancher A, et al. A prevalent POLG CAG microsatellite length allele in humans and African great apes. Mammalian genome. 2004; 15(6):492-502.Spelbrink JN, Toivonen JM, Hakkaart GA, Kurkela JM, Cooper HM, Lehtinen SK, et al. In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. Journal of Biological Chemistry. 2000; 275(32):24818-28.Williams AJ, Paulson HL. Polyglutamine neurodegeneration: protein misfolding revisited. Trends in neurosciences. 2008; 31(10):521-8.Luoma P, Eerola J, Ahola S, Hakonen A, Hellström O, Kivistö K, et al. Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease. Neurology. 2007; 69(11):1152-9.Heidari MM, Houshmand M, Hosseinkhani S, Nafissi S, Scheiber-Mojdehkar B, Khatami M. Association between trinucleotide CAG repeats of the DNA polymerase gene (POLG) with age of onset of Iranian Friedreich’s ataxia patients. Neurol Sci. 2008 Dec; 29(6):489-93.Heidari MM, Khatami M, Talebi AR. The POLG Gene Polymorphism in Iranian Varicocele-Associated Infertility Patients. Iran J Basic Med Sci. 2012 Mar; 15(2):739-44.Jensen M, Leffers H, Petersen JH, Nyboe Andersen A, Jorgensen N, Carlsen E, et al. Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Hum Reprod. 2004 Jan; 19(1):65-70.Taanman JW, Schapira AH. Analysis of the trinucleotide CAG repeat from the DNA polymerase gamma gene (POLG) in patients with Parkinson’s disease. Neurosci Lett. 2005 Mar 7; 376(1):56-9.Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 2008 Sep; 29(9):E150-72.Kumleh HH, Riazi GH, Houshmand M, Sanati MH, Gharagozli K, Shafa M. Complex I deficiency in Persian multiple sclerosis patients. Journal of the Neurological Sciences. 2006 4/15/; 243(1–2):65-9.Ebers GC, Sadovnick AD, Dyment DA, Yee IML, Willer CJ, Risch N. Parent-of-origin effect in multiple sclerosis: observations in half-siblings. The Lancet. 2004; 363(9423):1773-4.Harding A, Sweeney M, Miller D, Mumford C, Kellar-Wood H, Menard D, et al. Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain: a journal of neurology.1992; 115(4):979-89.Ahari SE, Houshmand M, Panahi MS, Kasraie S, Moin M, Bahar MA. Investigation on mitochondrial tRNA (Leu/Lys), NDI and ATPase 6/8 in Iranian multiple sclerosis patients. Cell Mol Neurobiol. 2007 Sep; 27(6):695-700.Mahad DJ, Ziabreva I, Campbell G, Lax N, White K, Hanson PS, et al. Mitochondrial changes within axons in multiple sclerosis. Brain: a journal of neurology. 2009 May; 132(Pt 5):1161-74

The Role of Mitochondrial DNA (mtDNA) in the Development of Diabetic Retinopathy (DR): A Systematic Review

Diabetic Retinopathy (DR) is the most prevalent health problem, which is influenced by environmental and genetic factors with an increasing prevalence. The current systematic review is focused on mtDNA modification, including polymorphism and mutation/deletion, with a direct effect on DR. This systematic search was initially done through PubMed, Cochrane, EMBASE, SCOPUS, and Web of Science without a restriction on the years of publication. The terms searched included ‘‘mtDNA’’, ‘‘mitochondrial DNA’’, ‘‘diabetes’’, ‘‘diabetic’’, ‘‘retina’’, and ‘‘diabetic retinopathy’’. Animal, cohort, cross-sectional, and in vitro studies, as well as case series, case reports, review articles, and Letters to Editor were excluded from this research. From 1528 resulting searched articles, only 12 papers were finally chosen as the case-control studies considering  mtDNA gene and DR. Actually, of these 12 articles, 8 studies were concerned with mtDNA polymorphisms (UCP1, UCP2, ROMO-1, and Mn-SOD) and 4 articles were related to mtDNA mutation (A3243G mutation in tRNALeu(UUR) gene and mtDNA deletion (ΔmtDNA 4977)). Some conflicting results were found between the selected genetic modifications of mtDNA, such as Mn-SOD, UCP1, ΔmtDNA 4977, tRNALeu (UUR), and ROMO-1. Finally, A3243G mutation in the tRNALeu (UUR) gene and rs660339 and V16A polymorphisms of UCP2 and Mn-SOD genes were respectively considered as the most important factors in the pathogenesis of DR.Â

The Role of Mitochondrial DNA (mtDNA) in the Development of Diabetic Retinopathy (DR): A Systematic Review

Diabetic Retinopathy (DR) is the most prevalent health problem, which is influenced by environmental and genetic factors with an increasing prevalence. The current systematic review is focused on mtDNA modification, including polymorphism and mutation/deletion, with a direct effect on DR. This systematic search was initially done through PubMed, Cochrane, EMBASE, SCOPUS, and Web of Science without a restriction on the years of publication. The terms searched included ‘‘mtDNA’’, ‘‘mitochondrial DNA’’, ‘‘diabetes’’, ‘‘diabetic’’, ‘‘retina’’, and ‘‘diabetic retinopathy’’. Animal, cohort, cross-sectional, and in vitro studies, as well as case series, case reports, review articles, and Letters to Editor were excluded from this research. From 1528 resulting searched articles, only 12 papers were finally chosen as the case-control studies considering  mtDNA gene and DR. Actually, of these 12 articles, 8 studies were concerned with mtDNA polymorphisms (UCP1, UCP2, ROMO-1, and Mn-SOD) and 4 articles were related to mtDNA mutation (A3243G mutation in tRNALeu(UUR) gene and mtDNA deletion (ΔmtDNA 4977)). Some conflicting results were found between the selected genetic modifications of mtDNA, such as Mn-SOD, UCP1, ΔmtDNA 4977, tRNALeu (UUR), and ROMO-1. Finally, A3243G mutation in the tRNALeu (UUR) gene and rs660339 and V16A polymorphisms of UCP2 and Mn-SOD genes were respectively considered as the most important factors in the pathogenesis of DR.

Novel MYO15A variants are associated with hearing loss in the two Iranian pedigrees

Background: Clinical genetic diagnosis of non-syndromic hearing loss (NSHL) is quite challenging. With regard to its high heterogeneity as well as large size of some genes, it is also really difficult to detect causative mutations using traditional approaches. One of the recent technologies called whole-exome sequencing (WES) has been thus developed in this domain to remove the limitations of conventional methods. Methods: This study was a report on a research study of two unrelated pedigrees with multiple affected cases of hearing loss (HL). Accordingly, clinical evaluations and genetic analysis were performed in both families. Results: The results of WES data analysis to uncover autosomal recessive non-syndromic hearing loss (ARNSHL) disease-causing variants was reported in the present study. Initial analysis identified two novel variants of MYO15A i.e. c.T6442A:p.W2148R and c.10504dupT:p.C3502Lfs*15 correspondingly which were later confirmed by Sanger validations and segregation analyses. According to online prediction tools, both identified variants seemed to have damaging effects. Conclusion: In this study, whole exome sequencing were used as a first approach strategy to identify the two novel variants in MYO15A in two Iranian families with ARNSHL

Erratum – Carrier Status for p.Gly61Glu and p.Arg368His CYP1B1 Mutations Causing Primary Congenital Glaucoma in Iran

This is an Erratum to "Carrier Status for p.Gly61Glu and p.Arg368His CYP1B1 Mutations Causing Primary Congenital Glaucoma in Iran" [J Ophthalmic Vis Res 2021;16(4):574–581] and does not have an abstract. Please download the PDF or view the article HTML

Carrier Status for p.Gly61Glu and p.Arg368His CYP1B1 Mutations Causing Primary Congenital Glaucoma in Iran

Purpose: To estimate carrier frequencies of CYP1B1 mutations p.Gly61Glu and p.Arg368His, respectively, in Talesh and the east of Guilan province in Iran with a maximum error of 2%. Previously, it was shown that these CYP1B1 mutations may be relatively prevalent in these regions. Methods: Population-based screenings were performed. DNA was extracted from saliva samples of 1036 individuals from Talesh and 3029 individuals from the east of Guilan. P.Gly61Glu and p.Arg368His screenings were performed, respectively, by RFLP and ARMS-based PCR protocols. For confirmation, the DNA of individuals with mutations was sequenced using the Sanger protocol. Results: Nine individuals from Talesh (0.86%; 95%CI: 0.45–1.64%) carried the p.Gly61Glu mutation, and 73 from the east of Guilan (2.41%; 95%CI: 1.91–3.04%) carried p.Arg368His. There was no significant difference in frequencies between urban and rural regions of the various cities, nor among four cities within the east of Guilan. Conclusion: The frequencies of p.Gly61Glu carriers in Talesh and of p.Arg368His carriers in the east of Guilan were within the 95% confidence interval of a previous study based on screenings of fewer individuals. The reliability of the recent estimates is higher, as the confidence interval for p.Gly61Glu decreased from 6.5% to 1.19% and the interval for p.Arg368His decreased from 4% to 1.13%. Based on the new findings, the maximum expected frequency of p.Gly61Glu carriers in Talesh is 1.64%, and of p.Arg368His carriers in the east of Guilan is 3%. The need for performing premarital screenings in the respective cities can be evaluated

Amino acid-mPEGs: Promising excipients to stabilize human growth hormone against aggregation

Objective(s): Today, the non-covalent PEGylation methods of protein pharmaceuticals attract more attention and possess several advantages over the covalent approach. In the present study, Amino Acid-mPEGs (aa-mPEGs) were synthesized, and the human Growth Hormone (hGH) stability profile was assessed in their presence and absence.Materials and Methods: aa-mPEGs were synthesized with different amino acids (Trp, Glu, Arg, Cys, and Leu) and molecular weights of polymers (2 and 5 KDa). The aa-mPEGs were analyzed with different methods. The physical and structural stabilities of hGH were analyzed by SEC and CD spectroscopy methods. Physical stability was assayed at different temperatures within certain intervals. Molecular dynamics (MD) simulation was used to realize the possible mode of interaction between protein and aa-mPEGs. The cell-based method was used to evaluate the cytotoxicity.Results: HNMR and FTIR spectroscopy indicated that aa-mPEGs were successfully synthesized. hGH as a control group is known to be stable at 4 °C; a pronounced change in monomer degradation is observed when stored at 25 °C and 37 °C. hGH:Glu-mPEG 2 kDa with a molar ratio of 1:1 to the protein solution can significantly increase the physical stability. The CD spectroscopy method showed that the secondary structure of the protein was preserved during storage. aa-mPEGs did not show any cytotoxicity activities. The results of MD simulations were in line with experimental results.Conclusion: This paper showed that aa-mPEGs are potent excipients in decreasing the aggregation of hGH. Glu-mPEG exhibited the best-stabilizing properties in a harsh environment among other aa-mPEGs