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Antibody neutralization and viral virulence in recurring dengue virus type 2 outbreaks

Wong SS, Abd-Jamil J, Abubakar S

Viral Immunol, 2007 Sep;20(3):359-68.
PMID: 17931106

Outbreaks involving dengue viruses (DENV) of the same genotype occur in a cyclical pattern in Malaysia. Two cycles of outbreaks involving dengue virus type 2 (DENV-2) of the same genotype occurred in the 1990s in the Klang Valley, Malaysia. Sera of patients from the first outbreak and sera of mice inoculated with virus from the same outbreak had poorer neutralization activity against virus of the second outbreak. Conversely, patient sera from the second outbreak showed higher neutralization titer against virus of the early outbreak. At subneutralizing concentrations, sera of mice immunized with second outbreak virus did not significantly enhance infection with viruses from the earlier outbreak. Amino acid substitution from valine to isoleucine at position 129 of the envelope protein (E), as well as threonine to alanine at position 117 and lysine to arginine at position 272 of the NS1 protein, differentiated viruses of the two outbreaks. These findings highlight the potential influence of specific intragenotypic variations in eliciting varied host immune responses against the different DENV subgenotypes. This could be an important contributing factor in the recurring homogenotypic dengue virus outbreaks seen in dengue-endemic regions.

Matched MeSH terms: Mutation, Missense
Fulltext First molecular genotyping of A302S mutation in the gamma aminobutyric acid (GABA) receptor in Aedes albopictus from Malaysia

Low VL, Vinnie-Siow WY, Lim Y AL, Tan TK, Leong CS, Chen CD, et al.

Trop Biomed, 2015 Sep;32(3):554-6.
PMID: 26695218 MyJurnal

Given the lack of molecular evidence in altered target-site insecticide resistance mechanism in Aedes albopictus (Skuse) worldwide, the present study aims to detect the presence of A302S mutation in the gene encoding the gamma aminobutyric acid receptor resistant to dieldrin (Rdl) in Ae. albopictus for the first time from its native range of South East Asia, namely Malaysia. World Health Organization (WHO) adult susceptibility bioassay indicated a relatively low level of dieldrin resistance (two-fold) in Ae. albopictus from Petaling Jaya, Selangor. However, PCR-RFLP and direct sequencing methods revealed the presence of the A302S mutation with the predomination of heterozygous genotype (40 out of 82 individuals), followed by the resistant genotype with 11 individuals. This study represents the first field evolved instance of A302S mutation in Malaysian insect species.

Matched MeSH terms: Mutation, Missense*
Fulltext Low efficacy of delthamethrin-treated net against Singapore Aedes aegypti is associated with kdr-type resistance

Pang SC, Chiang LP, Tan CH, Vythilingam I, Lam-Phua SG, Ng LC

Trop Biomed, 2015 Mar;32(1):140-50.
PMID: 25801264 MyJurnal

There has been a worldwide surge in the number and severity of dengue in the past decades. In Singapore, relentless vector control efforts have been put in to control the disease since the 1960's. Space spraying, fogging, chemical treatment and source reduction are some commonly used methodologies for controlling its vectors, particularly Aedes aegypti. Here, as we explored the use of a commercially available delthamethrin-treated net as an alternative strategy and the efficacy of the treated net was found to be limited. Through bioassays and molecular studies, the failure of the treated net to render high mortality rate was found to be associated with the knockdown resistance (kdr) mutation. This is the first report of kdr- mutations in Singapore's Ae. aegypti. At least one point mutation, either homozygous or heterozygous, at amino acid residue V1016G of DIIS6 or F1269C of DIIIS6 was detected in 93% of field strains of Ae. aegypti. Various permutations of wild type and mutant amino acids of the four alleles were found to result in varying degree of survival rate among local field Ae. aegypti when exposed to the deltamethrin treated net. Together with the association of higher survival rate with the presence of both V1016G and F1269C, the data suggest the role of these mutations in the resistance to the deltamethrin. The high prevalence of these mutations were confirmed in a country wide survey where 70% and 72% of the 201 Ae. aegypti analysed possessed the mutations at residues 1016 and 1269 respectively. The highest mutated frequency combination was found to be heterozygous alleles (VG/FC) at both residues 1016 and 1269 (37.8%), followed by homozygous mutation at allele 1269 (24.4%) and homozygous mutation at allele 1016 (22.9%). The kdr- type of resistance among the vector is likely to undermine the effectiveness of pyrethroids treated materials against these mosquitoes.

Matched MeSH terms: Mutation, Missense
Fulltext Monoclonal antibody-escape variant of dengue virus serotype 1: Genetic composition and envelope protein expression

Chem YK, Chua KB, Malik Y, Voon K

Trop Biomed, 2015 Jun;32(2):344-51.
PMID: 26691263 MyJurnal

Monoclonal antibody-escape variant of dengue virus type 1 (MabEV DEN-1) was discovered and isolated in an outbreak of dengue in Klang Valley, Malaysia from December 2004 to March 2005. This study was done to investigate whether DEN152 (an isolate of MabEV DEN-1) is a product of recombination event or not. In addition, the non-synonymous mutations that correlate with the monoclonal antibody-escape variant were determined in this study. The genomes of DEN152 and two new DEN-1 isolates, DENB04 and DENK154 were completely sequenced, aligned, and compared. Phylogenetic tree was plotted and the recombination event on DEN152 was investigated. DEN152 is sub-grouped under genotype I and is closely related genetically to a DEN-1 isolated in Japan in 2004. DEN152 is not a recombinant product of any parental strains. Four amino acid substitutions were unique only to DEN 152. These amino acid substitutions were (Ser)[326](Leu), (Ser)[340](Leu) at the deduced E protein, (Ile)[250](Thr) at NS1 protein, and (Thr)[41](Ser) at NS5 protein. Thus, DEN152 is an isolate of the emerging monoclonal antibody-escape variant DEN-1 that escaped diagnostic laboratory detection.

Matched MeSH terms: Mutation, Missense*
Fulltext Monitoring of the h275y mutation in pandemic influenza A(H1N1) 2009 strains isolated in Malaysia

Suppiah J, Yusof MA, Othman KA, Saraswathy TS, Thayan R, Kasim FM, et al.

Southeast Asian J. Trop. Med. Public Health, 2011 Jan;42(1):100-4.
PMID: 21323171

The 2009 pandemic influenza A(H1N1) infection in Malaysia was first reported in May 2009 and oseltamivir was advocated for confirmed cases in postexposure prophylaxis. However, there are cases of oseltamivir-resistance reported among H1N1-positive patients in other countries. Resistance is due to substitution of histidine by tyrosine at residue 275 (H275Y) of neuraminidase (NA). In this study, we have employed Sanger sequencing method to investigate the occurrence of mutations in NA segments of 67 pandemic 2009 A(H1N1) viral isolates from Malaysian patients that could lead to probable oseltamivir resistance. The sequencing analysis did not yield mutation at residue 275 for all 67 isolates indicating that our viral isolates belong to the wild type and do not confer resistance to oseltamivir.

Matched MeSH terms: Mutation, Missense*
Fulltext Genetical and comparative genomics of Brassica under altered Ca supply identifies Arabidopsis Ca-transporter orthologs

Graham NS, Hammond JP, Lysenko A, Mayes S, O Lochlainn S, Blasco B, et al.

Plant Cell, 2014 Jul;26(7):2818-30.
PMID: 25082855 DOI: 10.1105/tpc.114.128603

Although Ca transport in plants is highly complex, the overexpression of vacuolar Ca(2+) transporters in crops is a promising new technology to improve dietary Ca supplies through biofortification. Here, we sought to identify novel targets for increasing plant Ca accumulation using genetical and comparative genomics. Expression quantitative trait locus (eQTL) mapping to 1895 cis- and 8015 trans-loci were identified in shoots of an inbred mapping population of Brassica rapa (IMB211 × R500); 23 cis- and 948 trans-eQTLs responded specifically to altered Ca supply. eQTLs were screened for functional significance using a large database of shoot Ca concentration phenotypes of Arabidopsis thaliana. From 31 Arabidopsis gene identifiers tagged to robust shoot Ca concentration phenotypes, 21 mapped to 27 B. rapa eQTLs, including orthologs of the Ca(2+) transporters At-CAX1 and At-ACA8. Two of three independent missense mutants of BraA.cax1a, isolated previously by targeting induced local lesions in genomes, have allele-specific shoot Ca concentration phenotypes compared with their segregating wild types. BraA.CAX1a is a promising target for altering the Ca composition of Brassica, consistent with prior knowledge from Arabidopsis. We conclude that multiple-environment eQTL analysis of complex crop genomes combined with comparative genomics is a powerful technique for novel gene identification/prioritization.

Matched MeSH terms: Mutation, Missense
Fulltext Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women

Breast Cancer Association Consortium, Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, et al.

N Engl J Med, 2021 02 04;384(5):428-439.
PMID: 33471991 DOI: 10.1056/NEJMoa1913948

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.
METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.
RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.
CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

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 Congenital deafness: high prevalence of a V37I mutation in the GJB2 gene among deaf school children in Alor Setar

Ruszymah BHI, Wahida IF, Zakinah Y, Zahari Z, Norazlinda MD, Saim L, et al.

Med J Malaysia, 2005 Aug;60(3):269-74.
PMID: 16379178

Twenty percent of all childhood deafness is due to mutations in the GJB2 gene (Connexin 26). The aim of our study was to determine the prevalence and spectrum of GJB2 mutations in childhood deafness in Malaysia. We analyzed the GJB2 gene in 51 deaf students from Sekolah Pendidikan Khas Alor Setar, Kedah. Bidirectional sequencing indicates that 25% of our childhood deafness has mutation in their GJB2 gene. Sixty two percent of these children demonstrate V37I missense mutation. Interestingly, V37I mutation in the GJB2 gene have been reported as polymorphism in Western countries, however in our country it behaved as a potentially disease-causing missense mutation, causing childhood deafness as it was not found in the normal control.

Matched MeSH terms: Mutation, Missense*
Fulltext The prevalence of MTHFR 677C-->T missense mutation, total plasma homocysteine levels and associated risk factors in Malay subjects

Ling KH, Rosli R, Duraisamy G, Mohd Nasir MT

Med J Malaysia, 2003 Jun;58(2):243-54.
PMID: 14569745

The missense mutation of the methylenetetrahydrofolate reductase (MTHFR) gene 677C-->T is associated with modest elevation of homocysteine levels. The bio-ecogenetics factors of total homocysteine levels (tHcy) were investigated in a cross sectional study involving 53 randomly selected healthy Malay subjects. Results indicated that the prevalence of the homozygous 677T/T was 3.8% and heterozygous 677C/T was 17.0%. The levels of tHcy was higher in subjects aged more than 50 years (n = 7, 11.53 +/- 4.45 mumol/l) and in males (10.99 +/- 3.77 mumol/l) especially smoking males (12.19 +/- 3.62 mumol/l). THcy levels were low in the 3 pregnant subjects (4.44 mumol/l, p = 0.036) who were under folate supplementation.

Matched MeSH terms: Mutation, Missense/genetics*
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 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
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
An amino acid change in nsP4 of chikungunya virus confers fitness advantage in human cell lines rather than in Aedes albopictus

Fu JYL, Chua CL, Vythilingam I, Sulaiman WYW, Wong HV, Chan YF, et al.

J Gen Virol, 2019 11;100(11):1541-1553.
PMID: 31613205 DOI: 10.1099/jgv.0.001338

Chikungunya virus (CHIKV) has caused large-scale epidemics of fever, rash and arthritis since 2004. This unprecedented re-emergence has been associated with mutations in genes encoding structural envelope proteins, providing increased fitness in the secondary vector Aedes albopictus. In the 2008-2013 CHIKV outbreaks across Southeast Asia, an R82S mutation in non-structural protein 4 (nsP4) emerged early in Malaysia or Singapore and quickly became predominant. To determine whether this nsP4-R82S mutation provides a selective advantage in host cells, which may have contributed to the epidemic, the fitness of infectious clone-derived CHIKV with wild-type nsP4-82R and mutant nsP4-82S were compared in Ae. albopictus and human cell lines. Viral infectivity, dissemination and transmission in Ae. albopictus were not affected by the mutation when the two variants were tested separately. In competition, the nsP4-82R variant showed an advantage over nsP4-82S in dissemination to the salivary glands, but only in late infection (10 days). In human rhabdomyosarcoma (RD) and embryonic kidney (HEK-293T) cell lines coinfected at a 1 : 1 ratio, wild-type nsP4-82R virus was rapidly outcompeted by nsP4-82S virus as early as one passage (3 days). In conclusion, the nsP4-R82S mutation provides a greater selective advantage in human cells than in Ae. albopictus, which may explain its apparent natural selection during CHIKV spread in Southeast Asia. This is an unusual example of a naturally occurring mutation in a non-structural protein, which may have facilitated epidemic transmission of CHIKV.

Matched MeSH terms: Mutation, Missense*
Lafora disease in a Malaysian with a rare mutation in the EPM2A gene

Tee SK, Ong TL, Aris A, See SML, Leong HY, Khalid MKNM, et al.

Seizure, 2019 Apr;67:78-81.
PMID: 30947044 DOI: 10.1016/j.seizure.2019.03.012
Matched MeSH terms: Mutation, Missense
Fulltext Whole exome sequencing identifies compound heterozygous variants of CR2 gene in monozygotic twin patients with common variable immunodeficiency

Mat Ripen A, Ghani H, Chear CT, Chiow MY, Syed Yahya SNH, Kassim A, et al.

SAGE Open Med, 2020;8:2050312120922652.
PMID: 32547748 DOI: 10.1177/2050312120922652

Objectives: A pair of female Malay monozygotic twins who presented with recurrent upper respiratory tract infections, hepatosplenomegaly, bronchiectasis and bicytopenia were recruited in this study. Both patients were suspected with primary immunodeficiency diseases. However, the definite diagnosis was not clear due to complex disease phenotypes. The objective of this study was to identify the causative gene mutation in these patients.
Methods: Lymphocyte subset enumeration test and whole exome sequencing were performed.
Results: We identified a compound heterozygous CR2 mutation (c.1916G>A and c.2012G>A) in both patients. These variants were then confirmed using Sanger sequencing.
Conclusion: Whole exome sequencing analysis of the monozygotic twins revealed compound heterozygous missense mutations in CR2.

Matched MeSH terms: Mutation, Missense
Fulltext Low prevalence of CHEK2 gene mutations in multiethnic cohorts of breast cancer patients in Malaysia

Mohamad S, Isa NM, Muhammad R, Emran NA, Kitan NM, Kang P, et al.

PLoS One, 2015;10(1):e0117104.
PMID: 25629968 DOI: 10.1371/journal.pone.0117104

CHEK2 is a protein kinase that is involved in cell-cycle checkpoint control after DNA damage. Germline mutations in CHEK2 gene have been associated with increase in breast cancer risk. The aim of this study is to identify the CHEK2 gene germline mutations among high-risk breast cancer patients and its contribution to the multiethnic population in Malaysia. We screened the entire coding region of CHEK2 gene on 59 high-risk breast cancer patients who tested negative for BRCA1/2 germline mutations from UKM Medical Centre (UKMMC), Hospital Kuala Lumpur (HKL) and Hospital Putrajaya (HPJ). Sequence variants identified were screened further in case-control cohorts consisting of 878 unselected invasive breast cancer patients (180 Malays, 526 Chinese and 172 Indian) and 270 healthy individuals (90 Malays, 90 Chinese and 90 Indian). By screening the entire coding region of the CHEK2 gene, two missense mutations, c.480A>G (p.I160M) and c.538C>T (p.R180C) were identified in two unrelated patients (3.4%). Further screening of these missense mutations on the case-control cohorts unveiled the variant p.I160M in 2/172 (1.1%) Indian cases and 1/90 (1.1%) Indian control, variant p.R180C in 2/526 (0.38%) Chinese cases and 0/90 Chinese control, and in 2/180 (1.1%) of Malay cases and 1/90 (1.1%) of Malay control. The results of this study suggest that CHEK2 mutations are rare among high-risk breast cancer patients and may play a minor contributing role in breast carcinogenesis among Malaysian population.

Matched MeSH terms: Mutation, Missense*
Fulltext Missense Mutation of Brain Derived Neurotrophic Factor (BDNF) Alters Neurocognitive Performance in Patients with Mild Traumatic Brain Injury: A Longitudinal Study

Narayanan V, Veeramuthu V, Ahmad-Annuar A, Ramli N, Waran V, Chinna K, et al.

PLoS One, 2016;11(7):e0158838.
PMID: 27438599 DOI: 10.1371/journal.pone.0158838

The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen's d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.

Matched MeSH terms: Mutation, Missense/genetics*
Fulltext Mutations in the tail domain of MYH3 contributes to atrial septal defect

Maran S, Ee R, Faten SA, Sy Bing C, Khaw KY, Erin Lim SH, et al.

PLoS One, 2020;15(4):e0230982.
PMID: 32315303 DOI: 10.1371/journal.pone.0230982

Atrial septal defect (ASD) is one of the most common congenital heart defects diagnosed in children. Sarcomeric genes has been attributed to ASD and knockdown of MYH3 functionally homologues gene in chick models indicated abnormal atrial septal development. Here, we report for the first time, a case-control study investigating the role of MYH3 among non-syndromic ASD patients in contributing to septal development. Four amplicons which will amplifies the 40 kb MYH3 were designed and amplified using long range-PCR. The amplicons were then sequenced using indexed paired-end libraries on the MiSeq platform. The STREGA guidelines were applied for planning and reporting. The non-synonymous c. 3574G>A (p.Ala1192Thr) [p = 0.001, OR = 2.30 (1.36-3.87)] located within the tail domain indicated a highly conserved protein region. The mutant model of c. 3574G>A (p.Ala1192Thr) showed high root mean square deviation (RMSD) values compared to the wild model. To our knowledge, this is the first study to provide compelling evidence on the pathogenesis of MYH3 variants towards ASD hence, suggesting the crucial role of non-synonymous variants in the tail domain of MYH3 towards atrial septal development. It is hoped that this gene can be used as panel for diagnosis of ASD in future.

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

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