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Episodic positive selection in the Cam734 haplotype and low prevalence of the A144F mutation in Plasmodium falciparum chloroquine resistance transporter gene among Thai isolates

Buppan P, Seethamchai S, Kuamsab N, Jongwutiwes S, Putaporntip C

Trop Biomed, 2018 Dec 01;35(4):861-871.
PMID: 33601836

Chloroquine resistance transporter of Plasmodium falciparum (PfCRT) is a food vacuolar transmembrane protein that mediates susceptibility of the parasite to chloroquine. A mutation at K76T of the Pfcrt gene is a key determinant for chloroquine resistance phenotype. In the absence of drug pressure, in vitro growth rate of chloroquine-resistance parasites was outcompeted by wild-type parasites unless intragenic compensatory mutations occurred. Chloroquine-resistant P. falciparum bearing the Cam734 haplotype known to circulate in endemic areas of Cambodia bordering Thailand contains 9 mutations in Pfcrt and exhibits both chloroquine resistance and comparable growth rate to the chloroquine-sensitive 3D7 strain. To analyze the evolution of the Cam734 haplotype, codon-based analysis was performed by using the mixed effects model of evolution (MEME), branch-site random effects likelihood (BR-REL) and other related methods. Results revealed that the Cam734 haplotype has evolved distinctively from other known mutant haplotypes including the most common Dd2 haplotype in Southeast Asia. Evidence of episodic positive selection was detected at codon 144, characterized by c.[430G>T; 431C>T] (p.A144F), known to be indispensable for both chloroquine resistance and restoration of growth rate of the parasites. To survey the prevalence of mutations at codons 76 and 144 in Pfcrt among Thai isolates, restriction fragment analysis of 548 P. falciparum isolates collected from six endemic provinces of Thailand during 1991 and 2016 was performed. The 144F Pfcrt mutant was detected in 7 (1.28%) isolates. All Thai isolates analyzed herein harbored a mutation at codon 76 whilst the wild-type parasite was not found. The low prevalence of isolates bearing the mutation 144F in PfCRT could imply little or lack of survival advantage of this mutant in endemic areas of Thailand where the wild-type parasites seem to be absent or extremely rare.

Matched MeSH terms: Mutation
Fulltext DNA Methylation of Human Choline Kinase Alpha Promoter-Associated CpG Islands in MCF-7 Cells

Mohamed Sa'dom SAF, Raikundalia S, Shamsuddin S, See Too WC, Few LL

Genes (Basel), 2021 06 01;12(6).
PMID: 34205960 DOI: 10.3390/genes12060853

Choline kinase (CK) is the enzyme catalyzing the first reaction in CDP-choline pathway for the biosynthesis of phosphatidylcholine. Higher expression of the α isozyme of CK has been implicated in carcinogenesis, and inhibition or downregulation of CKα (CHKA) is a promising anticancer approach. This study aimed to investigate the regulation of CKα expression by DNA methylation of the CpG islands found on the promoter of this gene in MCF-7 cells. Four CpG islands have been predicted in the 2000 bp promoter region of ckα (chka) gene. Six CpG island deletion mutants were constructed using PCR site-directed mutagenesis method and cloned into pGL4.10 vectors for promoter activity assays. Deletion of CpG4C region located between -225 and -56 significantly increased the promoter activity by 4-fold, indicating the presence of important repressive transcription factor binding site. The promoter activity of methylated full-length promoter was significantly lower than the methylated CpG4C deletion mutant by 16-fold. The results show that DNA methylation of CpG4C promotes the binding of the transcription factor that suppresses the promoter activity. Electrophoretic mobility shift assay analysis showed that cytosine methylation at MZF1 binding site in CpG4C increased the binding of putative MZF1 in nuclear extract. In conclusion, the results suggest that DNA methylation decreased the promoter activity by promoting the binding of putative MZF1 transcription factor at CpG4C region of the ckα gene promoter.

Matched MeSH terms: Mutation
Fulltext Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, et al.

Am J Hum Genet, 2016 Oct 06;99(4):950-961.
PMID: 27666374 DOI: 10.1016/j.ajhg.2016.08.005

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

Matched MeSH terms: Mutation/genetics*; Frameshift Mutation/genetics
Fulltext Technical aspects in understanding effects of gamma irradiation on flower colour changes in Dendrobium Sonia

Sakinah Ariffin, Azhar Mohamad, Ratnam, Wickneswari

Jurnal Sains Nuklear Malaysia, 2012;24(1):91-101.
MyJurnal

Colour is one of the most important traits in orchids and has created great interest in breeding programmes. Gamma irradiation is an alternative way for generation of somaclonal variation for new flower colours. Phenotypic changes are usually observed during screening and selection of mutants. Understanding of targeted gene expression level and evaluation of the changes facilitate in the development of functional markers for selection of desired flower colour mutants. Four Dendrobium orchid sequences (NCBI accessions: AM490639, AY41319, FM209429 and DQ462460) were selected to design gene specific primers based on information for chalcone synthase (CHS) from NCBI database. Quantitative real-time PCR (qPCR) was used to understand flower colour expression quantitatively derived from the CHS gene activities in different flower tissues (petal and sepal) from control Dendrobium Sonia (red purple), mutant DS 35-1/M (purple pink) and mutant DS 35-WhiteA. It was found that expression of CHS gene was highest in sepals of white flowers and lowest in both sepals and petals of purple pink flowers. Genomic DNA was amplified and PCR products were sequenced, aligned and compared. Sequence variations of CHS partial gene in Dendrobium Sonia mutants with different flower colour showed that two protein positions have been changed as compared to the control. These non-synonymous mutations may have contributed to the colour alterations in the white and purple pink mutants. This paper describes important procedures to quantify gene expression such as RNA isolation (quantity and quality), cDNA synthesis and primer design steps for CHS genes.

Matched MeSH terms: Silent Mutation
Association of The IDH1 C.395G>A (R132H) Mutation with Histological Type in Malay Brain Tumors

Mohamed Yusoff AA, Zulfakhar FN, Sul’ain MD, Idris Z, Abdullah JM

Asian Pac J Cancer Prev, 2016 12 01;17(12):5195-5201.
PMID: 28125199

Background: Brain tumors, constituting one of the most deadly forms of cancer worldwide, result from the accumulation of multiple genetic and epigenetic alterations in genes and signaling pathways. Isocitrate dehydrogenase enzyme isoform 1 (IDH1) mutations are frequently identified in primary brain tumors and acute myeloid leukemia. Studies on IDH1 gene mutations have been extensively performed in various populations worldwide but not in Malaysia. This work was conducted to study the prevalence of IDH1 c.395G>A (R132H) hotspot mutations in a group of Malaysian patients with brain tumors in order to gain local data for the IDH1 mutation profile in our population. Methods: Mutation analysis of c.395G>A (R132H) of IDH1 was performed in 40 brain tumor specimens by the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP) and then verified by direct sequencing. Associations between the IDH1 c.395G>A (R132H) mutation and clinicopathologic characteristics were also analyzed. Results: The IDH1 c.395G>A (R132H) mutation was detected in 14/40 patients (35%). A significant association was found with histological tumor types, but not with age, gender and race. Conclusions: IDH1 is frequently mutated and associated with histological subtypes in Malay brain tumors.

Matched MeSH terms: DNA Mutational Analysis; Mutation
Fulltext The CRISPR Growth Spurt: from Bench to Clinic on Versatile Small RNAs

Bayat H, Omidi M, Rajabibazl M, Sabri S, Rahimpour A

J Microbiol Biotechnol, 2017 Feb 28;27(2):207-218.
PMID: 27840399 DOI: 10.4014/jmb.1607.07005

Clustered regulatory interspaced short palindromic repeats (CRISPR) in association with CRISPR-associated protein (Cas) is an adaptive immune system, playing a pivotal role in the defense of bacteria and archaea. Ease of handling and cost effectiveness make the CRISPR-Cas system an ideal programmable nuclease tool. Recent advances in understanding the CRISPR-Cas system have tremendously improved its efficiency. For instance, it is possible to recapitulate the chronicle CRISPR-Cas from its infancy and inaugurate a developed version by generating novel variants of Cas proteins, subduing off-target effects, and optimizing of innovative strategies. In summary, the CRISPR-Cas system could be employed in a number of applications, including providing model systems, rectification of detrimental mutations, and antiviral therapies.

Matched MeSH terms: Mutation
In silico analysis of nonsynonymous single nucleotide polymorphisms of the human adiponectin receptor 2 (ADIPOR2) gene

Solayman M, Saleh MA, Paul S, Khalil MI, Gan SH

Comput Biol Chem, 2017 Jun;68:175-185.
PMID: 28359874 DOI: 10.1016/j.compbiolchem.2017.03.005

Polymorphisms of the ADIPOR2 gene are frequently linked to a higher risk of developing diseases including obesity, type 2 diabetes and cardiovascular diseases. Though mutations of the ADIPOR2 gene are detrimental, there is a lack of comprehensive in silico analyses of the functional and structural impacts at the protein level. Considering the involvement of ADIPOR2 in glucose uptake and fatty acid oxidation, an in silico functional analysis was conducted to explore the possible association between genetic mutations and phenotypic variations. A genomic analysis of 82 nonsynonymous SNPs in ADIPOR2 was initiated using SIFT followed by the SNAP2, nsSNPAnalyzer, PolyPhen-2, SNPs&GO, FATHMM and PROVEAN servers. A total of 10 mutations (R126W, L160Q, L195P, F201S, L235R, L235P, L256R, Y328H, E334K and Q349H) were predicted to have deleterious effects on the ADIPOR2 protein and were therefore selected for further analysis. Theoretical models of the variants were generated by comparative modeling via MODELLER 9.16. A protein structural analysis of these amino acid variants was performed using SNPeffect, I-Mutant, ConSurf, Swiss-PDB Viewer and NetSurfP to explore their solvent accessibility, molecular dynamics and energy minimization calculations. In addition, FTSite was used to predict the ligand binding sites, while NetGlycate, NetPhos2.0, UbPerd and SUMOplot were used to predict post-translational modification sites. All of the variants showed increased free energy, though F201S exhibited the highest energy increase. The root mean square deviation values of the modeled mutants strongly indicated likely pathogenicity. Remarkably, three binding sites were detected on ADIPOR2, and two mutations at positions 328 and 201 were found in the first and second binding pockets, respectively. Interestingly, no mutations were found at the post-translational modification sites. These genetic variants can provide a better understanding of the wide range of disease susceptibility associated with ADIPOR2 and aid the development of new molecular diagnostic markers for these diseases. The findings may also facilitate the development of novel therapeutic elements for associated diseases.

Matched MeSH terms: Mutation
Fulltext Mitochondrial DNA Mutations in Grade II and III Glioma Cell Lines Are Associated with Significant Mitochondrial Dysfunction and Higher Oxidative Stress

Soon BH, Abdul Murad NA, Then SM, Abu Bakar A, Fadzil F, Thanabalan J, et al.

Front Physiol, 2017;8:231.
PMID: 28484394 DOI: 10.3389/fphys.2017.00231

The role of mitochondria in tumorigenesis has regained much attention as it could dysregulate cellular energetics, oxidative stress and apoptosis. However, the role of mitochondria in different grade gliomasis still unknown. This study aimed to identify mitochondrial DNA (mtDNA) sequence variations that could possibly affect the mitochondrial functions and also the oxidative stress status. Three different grades of human glioma cell lines and a normal human astrocyte cell line were cultured in-vitro and tested for oxidative stress biomarkers. Relative oxidative stress level, mitochondria activity, and mitochondrial mass were determined by live cell imaging with confocal laser scanning microscope using CM-H2DCFDA, MitoTracker Green, and MitoTracker Orange stains. The entire mitochondrial genome was sequenced using the AffymetrixGeneChip Human Mitochondrial Resequencing Array 2.0. The mitochondrial sequence variations were subjected to phylogenetic haplogroup assessment and pathogenicity of the mutations were predicted using pMUT and PolyPhen2. The Grade II astrocytoma cells showed increased oxidative stress wherea high level of 8-OHdG and oxidative stress indicator were observed. Simultaneously, Grade II and III glioma cells showed relatively poor mitochondria functions and increased number of mutations in the coding region of the mtDNA which could be due to high levels of oxidative stress in these cells. These non-synonymous mtDNA sequence variations were predicted to be pathogenic and could possibly lead to protein dysfunction, leading to oxidative phosphorylation (OXPHOS) impairment, mitochondria dysfunction and could create a vicious cycle of oxidative stress. The Grade IV cells had no missense mutation but preserved intact mitochondria and excellent antioxidant defense mechanisms thus ensuring better survival. In conclusion, Grade II and III glioma cells demonstrated coding region mtDNA mutations, leading to mitochondrial dysfunction and higher oxidative stress.

Matched MeSH terms: Mutation
Fulltext Absence of nucleotide alteration in region of exon 34 of NOTCH1 and NOTCH2 receptor genes analysed in oral cancer samples: a preliminary observation

Nor Nasyitah Ismail, Khairani Idah Mokhtar

Archives of Orofacial Sciences, 2010;5(1):17-23.
MyJurnal

Oral cancer is one of the common cancer cases identified in the developing countries. Genetic mutation and overexpression of certain genes and proteins have been associated in the development of this cancer. Notch signalling pathway is normally involved in controlling the development process of vertebrates and invertebrates; however, deregulation of this pathway was found to be responsible in the formation of certain cancers including oral cancers. Activation of this pathway requires binding of the ligands to its receptors. Four NOTCH receptors (NOTCH 1, 2, 3 and 4) have been identified in mammals. Disruptions within these molecules might interfere with the normal functions of Notch signalling pathway. Hence, this study was conducted to detect mutations of NOTCH1 and NOTCH2 receptor genes which might be occurring in the oral cancer cases obtained from the local population. DNA extracted from fresh-frozen tissue biopsy of the tongue and buccal mucosa from 10 confirmed cases of oral cancer were subjected for polymerase chain reaction (PCR) amplification using the specific sets of primers. The PCR products were sent for sequencing before final results were analysed.
Due to time and cost limitation, only two out of four NOTCH receptor genes; NOTCH1 and NOTCH2, were used in this analysis. The results revealed absence of nucleotide changes for both NOTCH receptor genes amplified from these oral cancer samples. More samples and further analysis looking into other regions in these genes are required to conclude the involvement of NOTCH receptor genes mutation in causing oral cancer.

Matched MeSH terms: Mutation
Fulltext The molecular genetics and pathogenesis of cystic fibrosis lung disease

Abdullah, S.

Buletin Persatuan Genetik Malaysia, 2006;12(1):10-17.
MyJurnal

Cystic Fibrosis (CF) is a life-threatening inherited disease that particularly affects the airways and digestive systems, which is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CF is considered as the most common autosomal recessive disorder in the Caucasian population. However, the prevalence of this disease amongst Asians is considered to be low, hence the lack of awareness of this disease amongst geneticists and physicians in Malaysia. This review will describe the features of CF, its molecular genetics, the current classification of CFTR mutation classes, the genotype-phenotype correlations, the effects of modifier genes, and the discourse of the disease pathogenesis, in the hope of raising public awareness of the condition and ultimately to improve the clinical and social care of those affected by CF in Malaysia.

Matched MeSH terms: Mutation
Fulltext Bcl-2 expression and clinico-pathological correlations in invasive ductal carcinoma of the breast

Al-Joudi, Fawwaz S., Iskandar Zulkarnain A.

Jurnal Sains Kesihatan Malaysia, 2010;8(2):59-64.
MyJurnal

Bcl-2 is an anti-apoptotic protein belonging to a family of proteins that act as regulators of apoptosis in mammalian cells. Bcl-2 expression has previously been reported in normal breast ductal cells and its involvement in the hormonal regulation of hyperplasia and involution was further suggested, and it was thought to be expressed through hormonedependent pathways. Bcl-2 is a cytoplasmic oncoprotein which is highly expressed in human solid tumours. In breast cancer cells, however, Bcl-2 expression is down regulated, the exact mechanism and the effects of which are not clearly defined, as bcl-2 expression appears to be inversely correlated with the presence of p53 mutations. This work aimed at investigating the expression of bcl-2 in invasive ductal carcinoma of the breast utilizing an immunohistochemistry assay as well as studying the clinical correlations of bcl-2. Bcl-2 was detected in 43.7% of 382 invasive ductal carcinoma study cases. Its expression correlated positively, with lower age of patients, higher histological grades, large tumour sizes, estrogen receptor positivity and progesterone receptor negativity. However, the statistical correlations were weak. With the data obtained, it was found that the expression of bcl-2 correlated with unfavourable prognoses. Furthermore, bcl-2 detection alone may not be very helpful in consolidating a clinical diagnosis.

59-64

Matched MeSH terms: Mutation
Genetic variation in the glucose-6-phosphate dehydrogenase gene in Kelantan Malays with neonatal jaundice

Mohd Yusoff, N., Choo, K.E., Ghazali, S., Ibrahim, I., Mohd Hussin, Z.A., Mohd Yunus, et al.

Malaysian Journal of Paediatrics and Child Health, 2000;12(1):11-15.
MyJurnal

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked red blood cell enzymopathy common in malaria endemic areas. Individuals affected by this disease show a wide variety of clinical signs including neonatal jaundice. In this preliminary report we describe the heterogeneity of G6PD deficient gene in neonatal jaundice in the Malay population in Kelantan. Thirteen G6PD deficient Malay neonates with hyperbilirubinemia were subjected to mutation analysis of the G6PD gene for known candidate mutations. Molecular defects were identified in the 13 patients studied. Though all of these were mis-sense mutations, identified nucleotide changes were heterogeneous. Six patients were found to have a C to T nucleotide change at nucleotide 563 of the G6PD gene (C563T), corresponding to G6PD Mediterranean; three cases had a single nucleotide change at T383C (G6PD Vanua Lava), two cases had G487A (G6PD Mahidol) and two cases had G1376T (G6PD Canton). These findings suggest that there are heterogeneous mutations of the G6PD gene associated with neonatal jaundice in the Malay population in Kelantan.

Matched MeSH terms: DNA Mutational Analysis; Mutation
Fulltext Hepatitis B Virus Genotypes and Mutations Affecting HBeAg Production: A Malaysian Perspective

Cheek, Ken Lim, So, Har Ton

Medicine & Health, 2007;2(1):1-25.
MyJurnal

Infection by hepatitis B virus (HBV) is a major global health-care problem. HBV is an accepted factor in the elevated risks for liver disease such as cirrhosis and development of hepatocellular carcinoma. This problem is particularly prevalent in the Asia-Pacific region which includes Malaysia. During infection, the hepatitis B e antigen (HBeAg) is produced in the hosts. This antigen is an important serological marker for diagnosing chronic hepatitis B. Seroconversion to anti-body (anti-HBe) corresponds to the improvement of disease prognosis. However, certain mutations such as the core promoter dual mutations (A1762G1764→T1762A1764), the codon 15 variants (C1858/ T1858) and the precore stop codon mutations (TGG→TAG) can affect the HBeAg expression. This has diagnostic and clinical implications. Besides that, the HBV can be grouped into eight genotypes (A to H). Moreover, genotypic subtypes and recombinants have been observed as well. Studies have observed that these can differ in their affiliations with the mutations above as well as with disease prognosis.

Matched MeSH terms: Mutation
Fulltext An immunohistochemical study of p53 in oral epithelium dysplasia and squamous cell carcinoma

Ma, M.S.

Malaysian Dental Journal, 2007;28(2):78-82.
MyJurnal

Squamous cell carcinoma (SCC) is the commonest cancer in the mouth. Multiple risk factors, such as smoking, alcohol consumption, irradiation, viruses infection and chronic irritation are thought to be responsible for the formation of oral squamous cell carcinoma. Although SCC can develop through a series of precancerous stages manifested as various degrees of epithelial dysplasia, this is not always the case. p53 is the commonest mutated gene in human cancers. Mis-sense mutation of the gene or complexing of the protein with viral or cellular proteins prolongs its half-life and leads to its detection by immunohistochemistry. This study was designed with the aim of demonstrating any possible relationship between p53 and oral squamous cell carcinoma by immunohistochemical staining techniques. A total of 66 specimens from the oral cavity (10 normal mucosa, 11 hyperkeratosis without dysplasia, 11 mild dysplasia, 11 moderate dysplasia, 10 severe dysplasia and 13 SCC) were examined for the presence of p53. The results show p53 was not expressed in normal mucosa, but was found with increasing frequency in increasingly severe dysplasia and SCC. In conclusion, this study shows p53 mutation is common in oral squamous cell carcinoma and probably occurs early in the multisteps of oral carcinogenesis.

Matched MeSH terms: Mutation
Fulltext Determination of RUNX2 single nucleotide polymorphism RS6930053 in class i, ii and iii malocclusions

Khairani Idah Mokhtar, Noraini Abu Bakar, Azrul Fazwan Kharuddin

International Medical Journal Malaysia, 2017;16(21):57-57.
MyJurnal

Runt-related transcription factor 2 (RUNX2) plays important roles in osteoblast
differentiation, tooth development and chondrocyte maturation; hence its involvement in
craniofacial development is paramount. Mutation in RUNX2 is implicated with cleidocranial
dysplasia; a bone development disorder, while single nucleotide polymorphism (SNP) in RUNX2 is
associated with Class II/2 malocclusion. This study aimed to determine RUNX2 SNP of DNA marker
(rs6930053) in malocclusion patients from local population. (Copied from article).

Matched MeSH terms: Mutation
Fulltext Evaluation of heterozygous Hb E and its interaction with deletional alpha thalassaemia in Kelantan

Nur Hidayah Muhamad Yasin, Majdan Ramli, Ilunihayati Ibrahim, Rosnah Bahar, Noraesah Mahmud, Siti Shahrum Muhamed Said, et al.

Journal of Biomedical and Clinical Sciences, 2017;2(202):35-37.
MyJurnal

Haemoglobin E (Hb E) is a variant of structurally abnormal haemoglobin that can be found very commonly in the Asian countries particularly the Southeast Asian [1]. [H1] Alpha thalassaemia is a red cell disorder which is caused by deletion or mutation of one or more of the four alpha globin genes leading to absence or decrease in production of alpha globin peptides [2]. This disorder is far more common in South East Asian regions and in Malaysia itself, and the gene frequency is about 4.1% [2]. The interactions of Hb E and alpha thalassaemia are evident in Kelantan which is bordered by southern Thailand. Using capillary electrophoresis (CE), a reduction of Hb E level is noticed as compared to Hb E heterozygotes. DNA analysis should be done to determine the presence of concurrent alpha thalassaemia variant. This study was done to evaluate haematological parameters using automated blood counters, morphology of red cells, Hb separation and quantitation of Hb fractions using CE and molecular analysis for alpha thalassemia. The study also aimed to discover cut off point of Hb E level in heterozygous Hb E patients with concurrent deletional alpha thalassaemia by CE.

Matched MeSH terms: Mutation
Fulltext Detection of Genetically Modified Organisms (GMOs) using molecular techniques in food and feed samples from Malaysia and Vietnam

Tung Nguyen, C.T., Son, R., Raha, A.R., Lai, O.M., Clemente Michael Wong, V.L.

International Food Research Journal, 2008;15(2):155-166.
MyJurnal

Food labeling in accordance with Novel Food Regulation has been enforced in the European Community since 1997 with a series of updated legislations namely, EC/258/97, EC/1139/98, EC/49/2000, EC/50/2000 and EC/1829/2003. Guidelines and labeling regulations for the use of GMOs materials in food and feed products has also been introduced in Malaysia and Vietnam. Therefore, the demand for the establishment and development of a robust and rapid operation procedure for GMO detection has increased recently in both countries. The procedure of GMO detection emphasizes not only on detection tests but also on confirmation assays. This study employed PCR technology for detection and direct DNA sequencing for confirmation procedures respectively. The results demonstrated for the first time the presence of GM plants with glyphosate-resistant trait led by the control of P35S promoter and NOS terminator in either Malaysian or Vietnamese feed with high frequency (20 positive samples out of 24 analyzed samples). The P35S promoter, EPSPS gene and NOS terminator sequences obtained showed some mutations on single-stranded and double-stranded targeted sequences caused by single nucleotide insertion or single nucleotide changes. These results reinforce the need for development of detection procedures to comply with food/feed labeling system.

Matched MeSH terms: Mutation
Fulltext Clinical and Mutational Analysis of the GCDH Gene in Malaysian Patients with Glutaric Aciduria Type 1

Abdul Wahab SA, Yakob Y, Abdul Azize NA, Md Yunus Z, Huey Yin L, Mohd Khalid MK, et al.

Biomed Res Int, 2016;2016:4074365.
PMID: 27672653

Glutaric aciduria type 1 (GA1) is an autosomal recessive metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase enzyme encoded by the GCDH gene. In this study, we presented the clinical and molecular findings of seven GA1 patients in Malaysia. All the patients were symptomatic from infancy and diagnosed clinically from large excretion of glutaric and 3-hydroxyglutaric acids. Bidirectional sequencing of the GCDH gene revealed ten mutations, three of which were novel (Gln76Pro, Glu131Val, and Gly390Trp). The spectrum of mutations included eight missense mutations, a nonsense mutation, and a splice site mutation. Two mutations (Gln76Pro and Arg386Gln) were homozygous in two patients with parental consanguinity. All mutations were predicted to be disease causing by MutationTaster2. In conclusion, this is the first report of both clinical and molecular aspects of GA1 in Malaysian patients. Despite the lack of genotype and phenotype correlation, early diagnosis and timely treatment remained the most important determinant of patient outcome.

Matched MeSH terms: Mutation, Missense
Fulltext First reported case of Haemoglobin-M Hyde Park in a Malay family living in Malaysia

Loong TY, Chong DL, Jamal AR, Murad NA, Sabudin RZ, Fun LC

EXCLI J, 2016;15:630-635.
PMID: 28096792 DOI: 10.17179/excli2016-613

Haemoglobin (Hb)-M Hyde Park, also known as Hb-M Akita is a rare type of hereditary Hb M due to autosomal dominant mutation of CAC>TAC on codon 92 of β globin gene resulting in the replacement of histidine by tyrosine on β globin chain. This variant Hb has a tendency to form methaemoglobin (metHb). The iron ion in metHb is oxidized to ferric (Fe3+) which is unable to carry oxygen and the patients manifest as cyanosis clinically. A 9-year-old Malay girl was incidentally found to be cyanotic when she presented to a health clinic. Laboratory investigations revealed raised methaemoglobin levels and Hb analysis findings were consistent with Hb-M Hyde Park. β gene sequencing confirmed a point mutation of CAC>TAC on codon 92 in one of the β genes. The family study done on the individuals with cyanosis showed similar findings. A diagnosis of heterozygous Hb-M Hyde Park was made. Patients with this variant Hb usually presented with cyanosis with mild haemolysis and maybe misdiagnosed as congenital heart disease. No further treatment is needed as patients are relatively asymptomatic. Although the disease is harmless in the heterozygous carriers but the offspring of the carriers may suffer severe haemolytic anaemia when the offspring also inherit other β haemoglobinopathies/thalassemia. This can happen due to high prevalence of β thalassemia carrier (3.5-4 %) found in Malaysia. At the time of writing, this is the first case of hereditary Hb-M Hyde Park diagnosed in a Malay family living in Malaysia.

Matched MeSH terms: Point Mutation
Mutational Profiles of F8 and F9 in a Cohort of Haemophilia A and Haemophilia B Patients in the Multi-ethnic Malaysian Population

Zahari M, Sulaiman SA, Othman Z, Ayob Y, Karim FA, Jamal R

Mediterr J Hematol Infect Dis, 2018;10(1):e2018056.
PMID: 30210749 DOI: 10.4084/MJHID.2018.056

Background: Haemophilia A (HA) and Haemophilia B (HB) are X-linked blood disorders that are caused by various mutations in the factor VIII (F8) and factor IX (F9) genes respectively. Identification of mutations is essential as some of the mutations are associated with the development of inhibitors. This study is the first comprehensive study of the F8 mutational profile in Malaysia.
Materials and methods: We analysed 100 unrelated HA and 15 unrelated HB patients for genetic alterations in the F8 and F9 genes by using the long-range PCR, DNA sequencing, and the multiplex-ligation-dependent probe amplification assays. The prediction software was used to confirm the effects of these mutations on factor VIII and IX proteins.
Results: 44 (53%) of the severe HA patients were positive for F8 intron 22 inversion, and three (3.6%) were positive for intron one inversion. There were 22 novel mutations in F8, including missense (8), frameshift (9), splice site (3), large deletion (1) and nonsense (1) mutations. In HB patients, four novel mutations were identified including the splice site (1), small deletion (1), large deletion (1) and missense (1) mutation.
Discussion: The mutational spectrum of F8 in Malaysian patients is heterogeneous, with a slightly higher frequency of intron 22 inversion in these severe HA patients when compared to other Asian populations. Identification of these mutational profiles in F8 and F9 genes among Malaysian patients will provide a useful reference for the early detection and diagnosis of HA and HB in the Malaysian population.

Matched MeSH terms: Mutation

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