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In silico study of missense variants of FANCA, FANCC and FANCG genes reveals high risk deleterious alleles predisposing to Fanconi anemia pathogenesis

Shahid M, Azfaralariff A, Zubair M, Abdulkareem Najm A, Khalili N, Law D, et al.

Gene, 2022 Feb 20;812:146104.
PMID: 34864095 DOI: 10.1016/j.gene.2021.146104

Among the 22 Fanconi anemia (FA) reported genes, 90% of mutational spectra were found in three genes, namely FANCA (64%), FANCC (12%) and FANCG (8%). Therefore, this study aimed to identify the high-risk deleterious variants in three selected genes (FANCA, FANCC, and FANCG) through various computational approaches. The missense variant datasets retrieved from the UCSC genome browser were analyzed for their pathogenicity, stability, and phylogenetic conservancy. A total of 23 alterations, of which 16 in FANCA, 6 in FANCC and one variant in FANCG, were found to be highly deleterious. The native and mutant structures were generated, which demonstrated a profound impact on the respective proteins. Besides, their pathway analysis predicted many other pathways in addition to the Fanconi anemia pathway, homologous recombination, and mismatch repair pathways. Hence, this is the first comprehensive study that can be useful for understanding the genetic signatures in the development of FA.

Matched MeSH terms: Mutation, Missense*
Fulltext RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Reijnders MRF, Ansor NM, Kousi M, Yue WW, Tan PL, Clarkson K, et al.

Am J Hum Genet, 2017 Sep 07;101(3):466-477.
PMID: 28886345 DOI: 10.1016/j.ajhg.2017.08.007

RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.

Matched MeSH terms: Mutation, Missense*
Fulltext MTHFR C677T polymorphism as a risk factor of neural tube defects in Malay: a case control study

Hayati AR, Zainal AI, Tan GC, Ong LC, Khoo TB

Med J Malaysia, 2008 Dec;63(5):379-83.
PMID: 19803295 MyJurnal

Major congenital malformations occur in about 3% of newborn. Several studies have suggested that homozygosity for the C677T methylenetetrahydrofolate reductase (MTHFR) variant is a potential risk factor for neural tube defects (NTDs). It has been hypothesized that the maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme. This association has not been found in some ethnic groups. In this study, we attempted to assess the association between NTDs and MTHFR C677T in Malaysian Malay population. Results show that MTHFR 677TT genotype was absent in both patient and control groups.

Matched MeSH terms: Mutation, Missense
Fulltext Generalized epilepsy with febrile seizure plus (GEFS+) spectrum: Novel de novo mutation of SCN1A detected in a Malaysian patient

Tan EH, Yusoff AA, Abdullah JM, Razak SA

J Pediatr Neurosci, 2012 May;7(2):123-5.
PMID: 23248692 DOI: 10.4103/1817-1745.102575

In this report, we describe a 15-year-old Malaysian male patient with a de novo SCN1A mutation who experienced prolonged febrile seizures after his first seizure at 6 months of age. This boy had generalized tonic clonic seizure (GTCS) which occurred with and without fever. Sequencing analysis of voltage-gated sodium channel a1-subunit gene, SCN1A, confirmed a homozygous A to G change at nucleotide 5197 (c.5197A > G) in exon 26 resulting in amino acid substitution of asparagines to aspartate at codon 1733 of sodium channel. The mutation identified in this patient is located in the pore-forming loop of SCN1A and this case report suggests missense mutation in pore-forming loop causes generalized epilepsy with febrile seizure plus (GEFS+) with clinically more severe neurologic phenotype including intellectual disabilities (mental retardation and autism features) and neuropsychiatric disease (anxiety disorder).

Matched MeSH terms: Mutation, Missense
Fulltext Molecular characterization of two Malaysian patients with Wiskott-Aldrich syndrome

Baharin MF, Kader Ibrahim SB, Yap SH, Abdul Manaf AM, Mat Ripen A, Dhaliwal JS

Malays J Pathol, 2015 Aug;37(2):153-8.
PMID: 26277674 MyJurnal

The Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency condition characterized by microthrombocytopenia, eczema and recurrent infections. It is caused by mutations in the Wiskott-Aldrich Syndrome protein (WASP) gene. We investigated two Malay boys who presented with congenital thrombocytopenia, eczema and recurrent infections. Here we report two cases of WASP mutation in Malaysia from two unrelated families. One had a novel missense mutation in exon 1 while the other had a nonsense mutation in exon 2. Both patients succumbed to diseaserelated complications. A differential diagnosis of WAS should be considered in any male child who present with early onset thrombocytopenia, especially when this is associated with eczema and recurrent infections.

Matched MeSH terms: Mutation, Missense
Comparative analysis of chromogenic vs clot.based one stage APTT assay for determination of factor VIII level

Baig MA, Swamy KB

Indian J Pathol Microbiol, 2021 1 13;64(1):123-127.
PMID: 33433421 DOI: 10.4103/IJPM.IJPM_900_19

Background: In the laboratory, factor VIII can be measured by three different methodologies, such as one-stage clotting assay, two-stage clotting assay, and chromogenic assay. These assays differ in ease of use, variety of reagents available, sensitivity to mild hemophilia A, and interference from lupus anticoagulants (LACs). Certain factor VIII gene mutations can cause discrepancy in results between one-stage activated partial thromboplastin time (APTT) and chromogenic assays.
Materials and Methods: The coagulometer for factor VIII assay is Sysmex CS-5100. All data were expressed as mean ± standard deviation (SD).
Results: A total of 135 cases were studied. Of these, 100 cases were of mild hemophilia A diagnosed by molecular genetics and, 15 cases were positive for LAC, which were confirmed by dilute Russell Viper venom test. Clot-based one-stage APTT assay showed 65% sensitivity and 80% specificity in diagnosing mild hemophilia A cases and out of 15 LAC cases, it showed false positivity in five cases. Chromogenic assay showed 85% sensitivity and 90% specificity in diagnosing mild hemophilia cases and was 100% specific in excluding LAC cases.
Conclusions: One-stage APTT assay is the most commonly used test for determining factor VIII levels but chromogenic assay are considered as the gold standard and recommended as the reference method by European Pharmacopoeia and ISTH subcommittee. Mild hemophilia A patients with missense mutations show discrepancy between the one-stage clot-based APTT assay and chromogenic assays for determination of factor VIII level and this can lead to misdiagnosis or misclassification of mild hemophilia A. Therefore, it is recommended that both the assays should be used in the evaluation of mild hemophilia cases.

Matched MeSH terms: Mutation, Missense
Clinical and genetic analysis of long QT syndrome in two Malay children

Wong AR, Zilfalil BA, Bhuiyan ZA

Med J Malaysia, 2019 08;74(4):341-343.
PMID: 31424047

Long QT syndrome (LQTS) is predominantly a genetic cardiac arrhythmia disorder. We report here our study on long QT syndrome from two children from Kelantan, Malaysia. Clinical and genetic findings of these two unrelated Malay children with LQTS is discussed. We found a Long QT, type 1 causal mutation, p.Ile567Thr in the KCNQ1 gene in the first child. A pathogenic mutation could not be detected in the second child, explaining the heterogeneity of this disease.

Matched MeSH terms: Mutation, Missense
Fulltext The Role of Surface Exposed Lysine in Conformational Stability and Functional Properties of Lipase from Staphylococcus Family

Ahmad NN, Ahmad Kamarudin NH, Leow ATC, Rahman RNZRA

Molecules, 2020 Aug 25;25(17).
PMID: 32854267 DOI: 10.3390/molecules25173858

Surface charge residues have been recognized as one of the stability determinants in protein. In this study, we sought to compare and analyse the stability and conformational dynamics of staphylococcal lipase mutants with surface lysine mutation using computational and experimental methods. Three highly mutable and exposed lysine residues (Lys91, Lys177, Lys325) were targeted to generate six mutant lipases in silico. The model structures were simulated in water environment at 25 °C. Our simulations showed that the stability was compromised when Lys177 was substituted while mutation at position 91 and 325 improved the stability. To illustrate the putative alterations of enzyme stability in the stabilising mutants, we characterized single mutant K325G and double mutant K91A/K325G. Both mutants showed a 5 °C change in optimal temperature compared to their wild type. Single mutant K325G rendered a longer half-life at 25 °C (T1/2 = 21 h) while double mutant K91A/K325G retained only 40% of relative activity after 12 h incubation. The optimal pH for mutant K325G was shifted from 8 to 9 and similar substrate preference was observed for the wild type and two mutants. Our findings indicate that surface lysine mutation alters the enzymatic behaviour and, thus, rationalizes the functional effects of surface exposed lysine in conformational stability and activity of this lipase.

Matched MeSH terms: Mutation, Missense
Molecular description of familial defective APOB-100 in Malaysia

Al-Khateeb AR, Mohd MS, Yusof Z, Zilfalil BA

Biochem Genet, 2013 Oct;51(9-10):811-23.
PMID: 23775634 DOI: 10.1007/s10528-013-9609-6

Familial ligand-defective apolipoprotein B-100 is characterized by elevated plasma low-density lipoprotein levels and premature heart disease. This study aims to determine apolipoprotein B gene mutations among Malaysians with clinical diagnoses of familial hypercholesterolemia and to compare the phenotype of patients with apolipoprotein B gene mutations to those with a low-density lipoprotein receptor gene mutation. A group of 164 patients with a clinical diagnosis of familial hypercholesterolemia was analyzed. Amplicons in exon 26 and exon 29 of the apolipoprotein B gene were screened for genetic variants using denaturing gradient high-performance liquid chromatography; 10 variants were identified. Five novel mutations were detected (p.Gln2485Arg, p.Thr3526Ala, p.Glu3666Lys, p.Tyr4343CysfsX221, and p.Arg4297His). Those with familial defective apolipoprotein had a less severe phenotype than those with familial hypercholesterolemia. An apolipoprotein gene defect is present among Malaysian familial hypercholesterolemics. Those with both mutations show a more severe phenotype than those with one gene defect.

Matched MeSH terms: Mutation, Missense
Fulltext Associations between primary hypertension and genes in the renin angiotensin system: a prospective two-center study in University Kebangsaan Malaysia Medical Center and International Medical University Cardiology Clinic

Norsham Juliana, Shaiful Yahaya, Abdul Latiff Mohamed, Roslan Harun

Malaysian Journal of Medicine and Health Sciences, 2010;6(2):19-24.
MyJurnal

This study targeted two candidate genes from the best known regulator of blood pressure; the rennin angiotensin system; the ACE gene I/D polymorphism and the angiotensinogen M235T polymorphism. The study aimed to determine the genotypes trend between two different populations; the primary hypertensive patients, and the normal populations. 126 subjects were involved in this study (86 primary hypertensive patients and 40 normal individuals). All demographic factors were considered and analyzed. Insertion/deletion polymorphisms of the ACE gene were determined by an assay based on the polymerase chain reaction (PCR). Polymorphism analysis using PCR-RFLP procedure was used to identify the missense mutation M235T of the AGT gene. All significant data was collected using standardized case report form. The association of the different genotypes and the subjects’ condition was analyzed using the chi squared and odds ratio analyses. In the pooled analysis of both groups, it was shown that the polymorphisms in these genes were significantly associated with the incidence of primary hypertension, p<0.05. Results also showed that the D allele of the ACE gene may be associated with increased risk of primary hypertension (p<0.05, O.R: 3.0 [C.I: 1.25 – 5.35]). The angiotensinogen M235T polymorphism also showed a significant result; the T allele is associated with increased risk of primary hypertension (p<0.05, O.R: 2.56[C.I: 1.55 – 5.28]). This knowledge of the candidate genes of rennin angiotensin system has rendered it possible to show that gene polymorphism in symphony leads to the individual risk of primary hypertension.
Keywords: ACE, M235T, rennin, hypertension

Study site: University Kebangsaan Malaysia Medical Center and International Medical University Cardiology Clinic

Matched MeSH terms: Mutation, Missense
Fulltext Lack of meaningful genotype-phenotype association in SCN1A-related infantile-onset epileptic encephalopathies

Siti Aishah Abdul Wahab, Yusnita Yakob, Khoo,Teik-Beng, Sangita Dharshini Terumalay, Vigneswari Ganesan, Teh,Chee-Ming, et al.

Neurology Asia, 2017;22(2):99-111.
MyJurnal

Background & Objective: SCN1A gene which encodes for sodium channel alpha 1 subunit has been
found to be the most common mutated gene in patients with epilepsy. This study aims to characterize the
SCN1A mutations as well as to describe genotype and phenotype association in children with SCN1Arelated
infantile-onset epileptic encephalopathies in Malaysia.

Methods: Children with infantile-onset
epileptic encephalopathy mostly suspected to have Dravet syndrome who had mutational analysis for
SCN1A gene from hospitals all over Malaysia were included in the study. Their epilepsy syndrome
diagnosis was classified into severe myoclonic epilepsy in infancy and its variants. Polymerase chain
reaction and bidirectional sequencing were used to identify SCN1A mutations.

Results: A total of 38
children with heterozygous mutations were analysed, 22 (57.9%) of which were novel mutations.
Truncated mutations were the most common mutation type (19, 50%). Other mutation types were
missense mutations (14, 36.8%), splice site mutations (4, 10.5%) and in-frame deletion (1, 2.6%). The
mean age of seizure onset was 4.7 months. Seizure following vaccination was observed in 26.3% of
the children. All of them had drug resistant epilepsy. There was no significant association between
the type of mutation with the syndromic diagnosis, age of seizure onset, tendency of the seizures to
cluster or having status epilepticus, mean age when developmental delay was observed and response
to various antiepileptic drugs.

Conclusion: This study expands the spectrum of SCN1A mutations and proves the importance of
SCN1A gene testing in diagnosing infantile-onset epileptic encephalopathies patients. Although, our
study does not support any clinically meaningful genotype-phenotype association for SCN1A-related
infantile-onset epileptic encephalopathies, the clinical characteristics of our cohort are similar to those
that have been described in previous studies.

Matched MeSH terms: Mutation, Missense
Highly deleterious variations in COX1, CYTB, SCG5, FK2, PRL and PGF genes are the potential adaptation of the immigrated African ostrich population

Al-Shuhaib MBS, Al-Kafajy FR, Badi MA, AbdulAzeez S, Marimuthu K, Al-Juhaishi HAI, et al.

Comput Biol Med, 2018 09 01;100:17-26.
PMID: 29960146 DOI: 10.1016/j.compbiomed.2018.06.019

Because of variable inconvenient living conditions in some places around the world, it is difficult to collect reliable physiological data for ostriches. Therefore, this study aims to provide a comprehensive in silico insight for the nature of polymorphism of important genetic loci that are related to physiological and reproductive traits. Sixty-nine mature ostriches ranging over half of Iraq were screened. Six exonic genetic loci, including cytochrome c oxidase I (COX1), cytochrome b (CYTB), secretogranin V (SCG5), feather keratin 2-like (FK2), prolactin (PRL) and placenta growth factor (PGF) were genotyped by PCR-single stranded conformation polymorphism (SSCP). Thirty-six novel SNPs, including seventeen nonsynonymous (ns) SNPs, were observed. Several computational software programs were utilized to assess the extent of the nsSNPs on their corresponding proteins structure, function and stability. The results showed several deleterious functional and stability changes in almost all the proteins studied. The total severity of each missense mutation was evaluated and compared with other nsSNPs accumulatively. It is evident from the extensive cumulative in silico computation that both p.E34D and p.E60K in PGF have the highest deleterious effect. The cumulative predictions from the present study are an impressive guide for the genotypes of African ostriches, which bypassed the expensive protocols for wet laboratory screening, to identify the effects of variants. To the best of our knowledge, this is the first investigation of its kind on the analyses and prediction outcome of missense mutations in African ostrich populations. The highly deleterious nsSNPs in the placenta growth factor are possible adaptive mutations which might be associated with adaptation in extreme and new environments. The flow and protocol of the computational predictions can be extended for various wild animals to identify the molecular nature of adaptations.

Matched MeSH terms: Mutation, Missense
Significance of BRAFV600E mutation in intra-axial brain tumor in Malaysian patients: case series and literature review

Mohamed Yusoff AA, Abd Radzak SM, Mohd Khair SZN, Abdullah JM

Exp Oncol, 2021 06;43(2):159-167.
PMID: 34190524

BACKGROUND: To date, BRAF mutations in brain tumor patients have not been characterized in the Malaysian population. Based on the numerous reported studies, there are main mutations that exist in BRAF gene in various types of cancers. A missense mutation in codon 600 of the BRAF nuclear oncogene (BRAFV600E) is the most prevalent hotspot point mutation that has been identified in multiple human malignancies.
AIM: We here aimed to find out the frequency of BRAFV600E mutation in a series of Malaysian patients with brain tumors and if any association exists between BRAFV600E mutation and clinicopathological features of patients.
MATERIAL AND METHODS: Fresh frozen tumor tissue samples from 50 Malaysian brain tumor patients were analyzed for BRAFV600E mutational status, and its correlation with clinicopathological features (including age, gender, and tumor localization such as intra-axial: within the brain substance or extra-axial: outside the brain substance) was examined.
RESULTS: The overall BRAFV600E mutation frequency was determined to be 22% (in 11 of 50 patients). BRAFV600E was significantly correlated with the tumor location group, which shows BRAFV600E was more frequent in the intra-axial tumor than the extra-axial tumor group. In this study, we also observed that male patients were slightly more susceptible to BRAFV600E mutation, and this mutation was predominant in patients of the age group

Matched MeSH terms: Mutation, Missense
Identification and characterization of neutralization epitopes at VP2 and VP1 of enterovirus A71

NikNadia N, Tan CW, Ong KC, Sam IC, Chan YF

J Med Virol, 2018 06;90(6):1164-1167.
PMID: 29457642 DOI: 10.1002/jmv.25061

Enterovirus A71 (EV-A71) neutralization escape mutants were generated with monoclonal antibody MAB979 (Millipore). The VP2-T141I and VP1-D14N substitutions were identified. Using reverse genetics, infectious clones with these substitutions were constructed and tested by neutralization assay with immune sera from mice and humans. The N-terminus VP1-14 is more important than EF loop VP2-141 in acute human infection, mainly because it recognised IgM present in acute infection. The N-terminus VP1 could be a useful target for diagnostics and therapeutic antibodies in acute infection.

Matched MeSH terms: Mutation, Missense
Fulltext Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia

Hall HN, Bengani H, Hufnagel RB, Damante G, Ansari M, Marsh JA, et al.

PLoS One, 2022;17(11):e0268149.
PMID: 36413568 DOI: 10.1371/journal.pone.0268149

Classical aniridia is a congenital and progressive panocular disorder almost exclusively caused by heterozygous loss-of-function variants at the PAX6 locus. We report nine individuals from five families with severe aniridia and/or microphthalmia (with no detectable PAX6 mutation) with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1. These mutations occurred de novo in 3/5 families, with the remaining families being compatible with autosomal dominant inheritance. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes. Substitutions of the same codon (Arg51) in MAB21L2, a close homolog of MAB21L1, cause severe ocular and skeletal malformations in humans and mice. The predicted nucleotidyltransferase function of MAB21L1 could not be demonstrated using purified protein with a variety of nucleotide substrates and oligonucleotide activators. Induced expression of GFP-tagged wildtype and mutant MAB21L1 in human cells caused only modest transcriptional changes. Mass spectrometry of immunoprecipitated protein revealed that both mutant and wildtype MAB21L1 associate with transcription factors that are known regulators of PAX6 (MEIS1, MEIS2 and PBX1) and with poly(A) RNA binding proteins. Arg51 substitutions reduce the association of wild-type MAB21L1 with TBL1XR1, a component of the NCoR complex. We found limited evidence for mutation-specific interactions with MSI2/Musashi-2, an RNA-binding proteins with effects on many different developmental pathways. Given that biallelic loss-of-function variants in MAB21L1 result in a milder eye phenotype we suggest that Arg51-altering monoallelic variants most plausibly perturb eye development via a gain-of-function mechanism.

Matched MeSH terms: Mutation, Missense
Fulltext BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Shimelis H, Mesman RLS, Von Nicolai C, Ehlen A, Guidugli L, Martin C, et al.

Cancer Res, 2017 Jun 01;77(11):2789-2799.
PMID: 28283652 DOI: 10.1158/0008-5472.CAN-16-2568

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

Matched MeSH terms: Mutation, Missense
Molecular diversity of HIV-1 and surveillance of transmitted drug resistance variants among treatment Naïve patients, 5 years after active introduction of HAART in Kuala Lumpur, Malaysia

Ong LY, Razak SN, Lee YM, Sri La Sri Ponnampalavanar S, Syed Omar SF, Azwa RI, et al.

J Med Virol, 2014 Jan;86(1):38-44.
PMID: 24127302 DOI: 10.1002/jmv.23772

Expansion of antiretroviral treatment programs have led to the growing concern for the development of antiretroviral drug resistance. The aims were to assess the prevalence of drug resistant HIV-1 variants and to identify circulating subtypes among HAART-naïve patients. Plasma specimens from N = 100 HIV+ HAART-naïve adult were collected between March 2008 and August 2010 and viral RNA were extracted for nested PCR and sequenced. PR-RT sequences were protein aligned and checked for transmitted drug resistance mutations. Phylogenetic reconstruction and recombination analysis were performed to determine the genotypes. Based on the WHO consensus guidelines, none of the recruited patients had any transmitted drug resistance mutations. When analyzed against the Stanford guidelines, 35% of patients had at least one reported mutation that may reduce drug susceptibility to PI (24%), NRTI (5%), and NNRTI (14%). The commonly detected mutation that may affect current first line therapy was V179D (3%), which may lead to reduced susceptibility to NNRTI. The predominant circulating HIV-1 genotypes were CRF01_AE (51%) and CRF33_01B (17%). The prevalence of unique recombinant forms (URF) was 7%; five distinct recombinant structures involving CRF01_AE and subtype B' were observed, among them a cluster of three isolates that could form a novel circulating recombinant form (CRF) candidate. Transmitted drug resistance prevalence among HAART-naïve patients was low in this cohort of patients in Kuala Lumpur despite introduction of HAART 5 years ago. Owing to the high genetic diversity, continued molecular surveillance can identify the persistent emergence of HIV-1 URF and novel CRF with significant epidemiological impact.

Matched MeSH terms: Mutation, Missense*
Fulltext High frequency of Plasmodium falciparum chloroquine resistance marker (pfcrt T76 mutation) in Yemen: an urgent need to re-examine malaria drug policy

Al-Mekhlafi AM, Mahdy MA, Al-Mekhlafi HM, Azazy AA, Fong MY

Parasit Vectors, 2011;4:94.
PMID: 21619624 DOI: 10.1186/1756-3305-4-94

Malaria remains a significant health problem in Yemen with Plasmodium falciparum being the predominant species which is responsible for 90% of the malaria cases. Despite serious concerns regarding increasing drug resistance, chloroquine is still used for the prevention and treatment of malaria in Yemen. This study was carried out to determine the prevalence of choloroquine resistance (CQR) of P. falciparum isolated from Yemen based on the pfcrt T76 mutation.

Matched MeSH terms: Mutation, Missense*
Fulltext Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D

Shmukler BE, Kedar PS, Warang P, Desai M, Madkaikar M, Ghosh K, et al.

Am J Hematol, 2010 Oct;85(10):824-8.
PMID: 20799361 DOI: 10.1002/ajh.21836

Familial distal renal tubular acidosis (dRTA) can be caused by mutations in the Cl2/HCO32 exchanger of the renal Type A intercalated cell, kidney AE1/SLC4A1. dRTA-associated AE1 mutations have been reported in families from North America, Europe, Thailand, Malaysia, Papua-New Guinea, Taiwan, and the Philippines, but not India. The dRTA mutation AE1 A858D has been detected only in the context of compound heterozygosity. We report here two unrelated Indian patients with combined hemolytic anemia and dRTA who share homozygous A858D mutations of the AE1/SLC4A1 gene. The mutation creates a novel restriction site that is validated for diagnostic screening.

Matched MeSH terms: Mutation, Missense*
Fulltext Factor IX mutations in haemophilia B patients in Malaysia: a preliminary study

Balraj P, Ahmad M, Khoo AS, Ayob Y

Malays J Pathol, 2012 Jun;34(1):67-9.
PMID: 22870602 MyJurnal

Haemophilia B is caused by coagulation defects in the factor IX gene located in Xq27.1 on the X chromosome. Identification of mutations contributing to defective factor IX may be advantageous for precise carrier and prenatal diagnosis. We studied 16 patients from 11 families, consisting of 8 patients of the Malay ethnic group, of which 6 were siblings. Factor IX mutations have not been previously reported in the Malay ethnic group. The functional region of the factor IX gene was sequenced and mutations were identified in either the exon or intronic regions in 15 of the patients. One novel mutation, 6660_6664delTTCTT was identified in siblings with moderate form of haemophilia B. Mutations identified in our patients when linked with disease severity were similar to findings in other populations. In summary, this preliminary data will be used to build a Malaysian mutation database which would facilitate genetic counseling.

Matched MeSH terms: Mutation, Missense

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