Displaying publications 1 - 20 of 49 in total

    The splicing of the pre-mRNA is one of the most essential and one of the several processes that characterized the exponential enrichment of proteomic diversity in higher eukaryotic organisms (Black, 2000, Graveley, 2001). For the splicing process, the introns must be removed and this is accurately carried out by an assembly of spliceosome
    Matched MeSH terms: Introns
  2. Chung KF, Leong WC, Rubite RR, Repin R, Kiew R, Liu Y, et al.
    Bot Stud, 2014 Dec;55(1):1.
    PMID: 28510906 DOI: 10.1186/1999-3110-55-1
    BACKGROUND: The picturesque limestone karsts across the Sino-Vietnamese border are renowned biodiversity hotspot, distinguished for extremely high endemism of calciphilous plants restricted to caves and cave-like microhabitats that have functioned as biological refugia on the otherwise harsh habitats. To understand evolutionary mechanisms underlying the splendid limestone flora, dated phylogeny is reconstructed for Asian Begonia, a species-rich genus on limestone substrates represented by no less than 60 species in southern China, using DNA sequences of nrITS and chloroplast rpL16 intron. The sampling includes 94 Begonia species encompassing most major Asian clades with a special emphasized on Chinese species.

    RESULTS: Except for two tuberous deciduous species and a species with upright stems, a majority of Sino-Vietnamese limestone Begonia (SVLB), including sect. Coelocentrum (19 species sampled) and five species of sect. Diploclinium, Leprosae, and Petermannia, are rhizomatous and grouped in a strongly supported and yet internally poorly resolved clade (Clade SVLB), suggesting a single evolutionary origin of the adaptation to limestone substrates by rhizomatous species, subsequent species radiation, and a strong tendency to retain their ancestral niche. Divergence-time estimates indicate a late Miocene diversification of Clade SVLB, coinciding with the onset of the East Asian monsoon and the period of extensive karstification in the area.

    CONCLUSIONS: Based on our phylogenetic study, Begonia sect. Coelocentrum is recircumscribed and expanded to include other members of the Clade SVLB (sect. Diploclinium: B. cavaleriei, B. pulvinifera, and B. wangii; sect. Leprosae: B. cylindrica and B. leprosa; sect. Petermannia: B. sinofloribunda). Because species of Clade SVLB have strong niche conservatism to retain in their ancestral habitats in cave-like microhabitats and Begonia are generally poor dispersers prone to diversify allopatrically, we propose that extensive and continuous karstification of the Sino-Vietnamese limestone region facilitated by the onset of East Asian monsoon since the late Miocene has been the major driving force for species accumulation via geographic isolation in Clade SVLB. Morphologically species of Clade SVLB differ mainly in vegetative traits without apparent adaptive value, suggesting that limestone Begonia radiation is better characterized as non-adaptive, an underappreciated speciation mode crucial for rapid species accumulations in organisms of low vagility and strong niche conservatism.

    Matched MeSH terms: Introns
  3. Forcina G, Camacho-Sanchez M, Tuh FYY, Moreno S, Leonard JA
    Heliyon, 2021 Jan;7(1):e05583.
    PMID: 33437884 DOI: 10.1016/j.heliyon.2020.e05583
    Background and aims: Wildlife conservation has focused primarily on species for the last decades. Recently, popular perception and laws have begun to recognize the central importance of genetic diversity in the conservation of biodiversity. How to incorporate genetic diversity in ongoing monitoring and management of wildlife is still an open question.

    Methods: We tested a panel of multiplexed, high-throughput sequenced introns in the small mammal communities of two UNESCO World Heritage Sites on different continents to assess their viability for large-scale monitoring of genetic variability in a spectrum of diverse species. To enhance applicability across other systems, the bioinformatic pipeline for primer design was outlined.

    Results: The number of loci amplified and amplification evenness decreased as phylogenetic distance increased from the reference taxa, yet several loci were still variable across multiple mammal orders.

    Conclusions: Genetic variability found is informative for population genetic analyses and for addressing phylogeographic and phylogenetic questions, illustrated by small mammal examples here.

    Matched MeSH terms: Introns
  4. Bunawan H, Yen CC, Yaakop S, Noor NM
    BMC Res Notes, 2017 Jan 26;10(1):67.
    PMID: 28126013 DOI: 10.1186/s13104-017-2379-1
    The chloroplastic trnL intron and the nuclear internal transcribed spacer (ITS) region were sequenced for 11 Nepenthes species recorded in Peninsular Malaysia to examine their phylogenetic relationship and to evaluate the usage of trnL intron and ITS sequences for phylogenetic reconstruction of this genus.
    Matched MeSH terms: Introns/genetics*
  5. Duff-Farrier CRA, Mbanzibwa DR, Nanyiti S, Bunawan H, Pablo-Rodriguez JL, Tomlinson KR, et al.
    Mol Biotechnol, 2019 Feb;61(2):93-101.
    PMID: 30484144 DOI: 10.1007/s12033-018-0139-7
    Cassava brown streak disease (CBSD) has major impacts on yield and quality of the tuberous roots of cassava in Eastern and Central Arica. At least two Potyviridae species cause the disease: Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV). Cloned viral genome sequences known as infectious clones (ICs) have been important in the study of other viruses, both as a means of standardising infectious material and characterising viral gene function. IC construction is often technically challenging for Potyviridae due to sequence instability in E. coli. Here, we evaluate three methods for the construction of infectious clones for CBSD. Whilst a simple IC for in vitro transcription was made for UCBSV isolate 'Kikombe', such an approach failed to deliver full-length clones for CBSV isolates 'Nampula' or 'Tanza', necessitating more complex approaches for their construction. The ICs successfully generated symptomatic infection in the model host N. benthamiana and in the natural host cassava. This shows that whilst generating ICs for CBSV is still a technical challenge, a structured approach, evaluating both in vitro and in planta transcription systems should successfully deliver ICs, allowing further study into the symptomology and virulence factors in this important disease complex.
    Matched MeSH terms: Introns/genetics
  6. Alina MF, Azma RZ, Norunaluwar J, Azlin I, Darnina AJ, Cheah FC, et al.
    J Hum Genet, 2020 Mar;65(3):263-270.
    PMID: 31863082 DOI: 10.1038/s10038-019-0700-7
    G6PD deficiency is the commonest enzyme deficiency found in humans. Current diagnostic methods lack sensitivity to detect all cases of G6PD deficiency. We evaluated the reverse dot blot flow-through hybridisation assay designed to detect simultaneously multiple known G6PD mutations in a group of Malaysian neonates. Archival DNA samples from 141 G6PD-deficient neonates were subjected to reverse dot blot flow-through hybridisation assay using the GenoArray Diagnostic Kit (Hybribio Limited, Hong Kong) and DNA sequencing. The method involved PCR amplification of 5 G6PD exons using biotinylated primers, hybridisation of amplicons to a membrane containing oligoprobes designed for G6PD mutations known to occur in the Malaysian population and colour detection by enzyme immunoassay. The assay detected 13 of the 14 G6PD mutations and genotyped 133 (94.3%) out of 141 (102 males, 39 females) cases. Among the 39 female G6PD-deficient neonates, there were 7 homozygous and 6 compound heterozygous cases. The commonest alleles were G6PD Viangchan 871G > A (21%) and G6PD Mahidol 487G > A(20%) followed by G6PD Mediterranean 563C > T, (14%), G6PD Vanua Lava 383T > C (12%), G6PD Canton 1376G > T (10%), G6PD Orissa 131C > G (6.3%) G6PD Coimbra 592C > T (5.6%) plus 6 other mutations. DNA sequencing of remaining cases revealed 6 cases of intron 11 nt 93C > T not previously reported in Malaysia and two novel mutations, one case each of nt 1361G > T and nt 1030G > A. We found the reverse dot blot assay easy to perform, rapid, accurate and reproducible, potentially becoming an improved diagnostic test for G6PD deficiency.
    Matched MeSH terms: Introns/genetics
  7. Sahebi M, Hanafi MM, van Wijnen AJ, Azizi P, Abiri R, Ashkani S, et al.
    Gene, 2016 Aug 10;587(2):107-19.
    PMID: 27154819 DOI: 10.1016/j.gene.2016.04.057
    Alternative pre-mRNA splicing provides a source of vast protein diversity by removing non-coding sequences (introns) and accurately linking different exonic regions in the correct reading frame. The regulation of alternative splicing is essential for various cellular functions in both pathological and physiological conditions. In eukaryotic cells, this process is commonly used to increase proteomic diversity and to control gene expression either co- or post-transcriptionally. Alternative splicing occurs within a megadalton-sized, multi-component machine consisting of RNA and proteins; during the splicing process, this complex undergoes dynamic changes via RNA-RNA, protein-protein and RNA-protein interactions. Co-transcriptional splicing functionally integrates the transcriptional machinery, thereby enabling the two processes to influence one another, whereas post-transcriptional splicing facilitates the coupling of RNA splicing with post-splicing events. This review addresses the structural aspects of spliceosomes and the mechanistic implications of their stepwise assembly on the regulation of pre-mRNA splicing. Moreover, the role of phosphorylation-based, signal-induced changes in the regulation of the splicing process is demonstrated.
    Matched MeSH terms: Introns
  8. Norlia B., Norwati M., Norwati A., Mohd Rosli H., Norihan M. S.
    This study was part of the larger studies to isolate and characterize gene related to flowering in teak. This study isolated differentially expressed genes of teak flowering tissues. One of the genes encodes plant protein kinases highly homologous to the AtSK-II of Arabidopsis GSK3/SHAGGY subfamily. The gene was named as Tectona grandis SHAGGY kinase (Tg-SK). The protein sequence of this gene contained the characteristic catalytic domain of GSK-3/SHAGGY protein kinase. The gene also shows the same genomic organization of 11 introns and 12 exons. Although the size of the introns varies, the positions of exon/intron boundaries are very similar to AtSK-II. The discovery of this gene in teak, which is a forest tree species, supports the hypothesis, which suggested the gene is found in all eukaryotes.
    Matched MeSH terms: Introns
  9. Yusof, R., Abdul Rahman, P.S., Rahim, Z.H.A.
    Ann Dent, 1999;6(1):-.
    The application of PCR technique in genetic screening was demonstrated using the genetic materials from buccal cells of the students in the class. Two factors were taken into consideration when designing the experiments. The DNA region to be amplified should not be associated with any disease state. This is to eliminate any emotional and ethical problems associated with the experiments. In this practical, the presence and absence of a 38 bp sequence in the intron of COLIA2 gene were studied. The students were also shown on how to analyse the presence of homozygous and heterozygous alleles and the genetic variations that might be observed in the different ethnic groups of students. Another factor was the time taken to complete the experiment. Our experience showed that this experiment would take at least six hours to obtain and analyse the results. It is therefore suitable to be used in class teaching.
    Matched MeSH terms: Introns
  10. 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: Introns
  11. Gan HM, Thomas BN, Cavanaugh NT, Morales GH, Mayers AN, Savka MA, et al.
    PeerJ, 2017;5:e4030.
    PMID: 29158974 DOI: 10.7717/peerj.4030
    In industry, the yeast Rhodotorula mucilaginosa is commonly used for the production of carotenoids. The production of carotenoids is important because they are used as natural colorants in food and some carotenoids are precursors of retinol (vitamin A). However, the identification and molecular characterization of the carotenoid pathway/s in species belonging to the genus Rhodotorula is scarce due to the lack of genomic information thus potentially impeding effective metabolic engineering of these yeast strains for improved carotenoid production. In this study, we report the isolation, identification, characterization and the whole nuclear genome and mitogenome sequence of the endophyte R. mucilaginosa RIT389 isolated from Distemonanthus benthamianus, a plant known for its anti-fungal and antibacterial properties and commonly used as chewing sticks. The assembled genome of R. mucilaginosa RIT389 is 19 Mbp in length with an estimated genomic heterozygosity of 9.29%. Whole genome phylogeny supports the species designation of strain RIT389 within the genus in addition to supporting the monophyly of the currently sequenced Rhodotorula species. Further, we report for the first time, the recovery of the complete mitochondrial genome of R. mucilaginosa using the genome skimming approach. The assembled mitogenome is at least 7,000 bases larger than that of Rhodotorula taiwanensis which is largely attributed to the presence of large intronic regions containing open reading frames coding for homing endonuclease from the LAGLIDADG and GIY-YIG families. Furthermore, genomic regions containing the key genes for carotenoid production were identified in R. mucilaginosa RIT389, revealing differences in gene synteny that may play a role in the regulation of the biotechnologically important carotenoid synthesis pathways in yeasts.
    Matched MeSH terms: Introns
  12. Ang GY, Yu CY, Subramaniam V, Abdul Khalid MI, Tuan Abdu Aziz TA, Johari James R, et al.
    PLoS One, 2016;11(10):e0164169.
    PMID: 27798644 DOI: 10.1371/journal.pone.0164169
    The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme's activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.
    Matched MeSH terms: Introns
  13. Avin FA, Subha B, Tan YS, Braukmann TWA, Vikineswary S, Hebert PDN
    Ecol Evol, 2017 09;7(17):6972-6980.
    PMID: 28904776 DOI: 10.1002/ece3.3049
    DNA barcoding involves the use of one or more short, standardized DNA fragments for the rapid identification of species. A 648-bp segment near the 5' terminus of the mitochondrial cytochrome c oxidase subunit I (COI) gene has been adopted as the universal DNA barcode for members of the animal kingdom, but its utility in mushrooms is complicated by the frequent occurrence of large introns. As a consequence, ITS has been adopted as the standard DNA barcode marker for mushrooms despite several shortcomings. This study employed newly designed primers coupled with cDNA analysis to examine COI sequence diversity in six species of Pleurotus and compared these results with those for ITS. The ability of the COI gene to discriminate six species of Pleurotus, the commonly cultivated oyster mushroom, was examined by analysis of cDNA. The amplification success, sequence variation within and among species, and the ability to design effective primers was tested. We compared ITS sequences to their COI cDNA counterparts for all isolates. ITS discriminated between all six species, but some sequence results were uninterpretable, because of length variation among ITS copies. By comparison, a complete COI sequences were recovered from all but three individuals of Pleurotus giganteus where only the 5' region was obtained. The COI sequences permitted the resolution of all species when partial data was excluded for P. giganteus. Our results suggest that COI can be a useful barcode marker for mushrooms when cDNA analysis is adopted, permitting identifications in cases where ITS cannot be recovered or where it offers higher resolution when fresh tissue is. The suitability of this approach remains to be confirmed for other mushrooms.
    Matched MeSH terms: Introns
  14. Yang W, Lee PP, Thong MK, Ramanujam TM, Shanmugam A, Koh MT, et al.
    Clin Genet, 2015 Dec;88(6):542-9.
    PMID: 25534311 DOI: 10.1111/cge.12553
    Familial multiple intestinal atresias is an autosomal recessive disease with or without combined immunodeficiency. In the last year, several reports have described mutations in the gene TTC7A as causal to the disease in different populations. However, exact correlation between different genotypes and various phenotypes are not clear. In this study, we report identification of novel compound heterozygous mutations in TTC7A gene in a Malay girl with familial multiple intestinal atresias and severe combined immunodeficiency (MIA-SCID) by whole exome sequencing. We found two mutations in TTC7A: one that destroyed a putative splicing acceptor at the junction of intron 17/exon 18 and one that introduced a stop codon that would truncate the last two amino acids of the encoded protein. Reviewing the recent reports on TTC7A mutations reveals correlation between the position and nature of the mutations with patient survival and clinical manifestations. Examination of public databases also suggests carrier status for healthy individuals, making a case for population screening on this gene, especially in populations with suspected frequent founder mutations.
    Matched MeSH terms: Introns
  15. Norafiza Zainuddin, Maizatul Akma Mamat, Norlelawati A. Talib
    Schizophrenia is a devastating mental disorder that affects people’s normal life with heterogeneous features of its clinical presentation, as well as its molecular attribute. In order to identify the potential molecular aberration, particularly single nucleotide polymorphism (SNP) which could be important in the aetiology of schizophrenia, polymerase chain reaction (PCR)-DNA sequencing approach was utilized for targeting the exon (and intron) 9 of the Hermansky-Pudlak syndrome type 4 (HPS4) gene. DNAs were extracted from peripheral blood of nine schizophrenic patients and one normal individual prior to PCR-DNA sequencing. Following DNA sequencing, a SNP (A>G) which is rs713998 at nucleotide position 22618 of exon 9 of the HPS4 gene was observed in eight schizophrenia samples. Moreover, DNA sequencing results also revealed an intronic aberration/SNP which is rs3747129 (C>T) at nucleotide position 22789 of intron 9 of the HPS4 gene in four schizophrenia samples. A SNP which is rs739289 (G>T) at nucleotide position 22677 of the intron was also found in eight schizophrenia samples. The importance of both the exonic and intronic aberrations is yet to be confirmed with further research involving larger population and other relevant clinical parameters. That notwithstanding, these preliminary results suggested that single nucleotide aberrations, particularly SNPs might have a role in the development of schizophrenia
    Matched MeSH terms: Introns
  16. Wan Khairunnisa Wan Juhari, Khairul Bariah Ahmad Amin Noordin, Wan Faiziah Wan Abdul Rahman, Andee Dzulkarnaen Zakaria, Ahmad Shanwani Mohd Sidek, Muhammad Radzi Abu Hassan, et al.
    Background: Hereditary nonpolyposis colorectal cancer (HNPCC) also known as Lynch syndrome is commonly caused by genetic alterations in any of the four mismatch repair (MMR) genes; MLH1, MSH2, MSH6 and PMS2. This is the first study aimed to investigate genetic variants in Malay HNPCC families. Methods: Six Malay HNPCC families who fulfilled any of the Bethesda criteria were recruited into this study. A total of 3 ml of blood was withdrawn from each patient in the families. The samples were further analyzed using polymerase chain reaction and direct sequencing of the selected exons of MLH1 and MSH2 genes. Results: Two missense mutations and four single nucleotide polymorphisms (SNPs) were identified in six patients. These variants in the MLH1 and MSH2 genes were identified in four families who met the revised Bethesda guidelines. In two families, no mutation and polymorphism was identified in both the exon and intron of the respective genes. Of the mutations and polymorphisms identified, five have never been reported in Malay HNPCC families before. A missense mutation was detected in exon 5 of the MLH1 gene, c.394G>C (p.Asp132His) and four mutations and polymorphisms were detected in the MSH2 gene; heterozygous c.211+98T>C and c.211+9C>G and homozygous c.211+98T>C and c.211+9C>G, c.367-86A>C and c.382C>G. Conclusion: The results represented a new spectrum of mutations and polymorphisms in the Malay HNPCC families. However, a larger study involving additional families and analysis is required to determine the impact and nature of the identified mutations and polymorphisms.
    Matched MeSH terms: Introns
  17. Ozyigit II, Filiz E, Vatansever R, Kurtoglu KY, Koc I, Öztürk MX, et al.
    Front Plant Sci, 2016;7:301.
    PMID: 27047498 DOI: 10.3389/fpls.2016.00301
    Among major reactive oxygen species (ROS), hydrogen peroxide (H2O2) exhibits dual roles in plant metabolism. Low levels of H2O2 modulate many biological/physiological processes in plants; whereas, its high level can cause damage to cell structures, having severe consequences. Thus, steady-state level of cellular H2O2 must be tightly regulated. Glutathione peroxidases (GPX) and ascorbate peroxidase (APX) are two major ROS-scavenging enzymes which catalyze the reduction of H2O2 in order to prevent potential H2O2-derived cellular damage. Employing bioinformatics approaches, this study presents a comparative evaluation of both GPX and APX in 18 different plant species, and provides valuable insights into the nature and complex regulation of these enzymes. Herein, (a) potential GPX and APX genes/proteins from 18 different plant species were identified, (b) their exon/intron organization were analyzed, (c) detailed information about their physicochemical properties were provided, (d) conserved motif signatures of GPX and APX were identified, (e) their phylogenetic trees and 3D models were constructed, (f) protein-protein interaction networks were generated, and finally (g) GPX and APX gene expression profiles were analyzed. Study outcomes enlightened GPX and APX as major H2O2-scavenging enzymes at their structural and functional levels, which could be used in future studies in the current direction.
    Matched MeSH terms: Introns
  18. Song BK, Hein I, Druka A, Waugh R, Marshall D, Nadarajah K, et al.
    Funct. Integr. Genomics, 2009 Feb;9(1):97-108.
    PMID: 18633654 DOI: 10.1007/s10142-008-0091-x
    Common wild rice (Oryza rufipogon) plays an important role by contributing to modern rice breeding. In this paper, we report the sequence and analysis of a 172-kb genomic DNA region of wild rice around the RM5 locus, which is associated with the yield QTL yld1.1. Comparative sequence analysis between orthologous RM5 regions from Oryza sativa ssp. japonica, O. sativa ssp. indica and O. rufipogon revealed a high level of conserved synteny in the content, homology, structure, orientation, and physical distance of all 14 predicted genes. Twelve of the putative genes were supported by matches to proteins with known function, whereas two were predicted by homology to rice and other plant expressed sequence tags or complementary DNAs. The remarkably high level of conservation found in coding, intronic and intergenic regions may indicate high evolutionary selection on the RM5 region. Although our analysis has not defined which gene(s) determine the yld1.1 phenotype, allelic variation and the insertion of transposable elements, among other nucleotide changes, represent potential variation responsible for the yield QTL. However, as suggested previously, two putative receptor-like protein kinase genes remain the key suspects for yld1.1.
    Matched MeSH terms: Introns/genetics
  19. Courage C, Oliver KL, Park EJ, Cameron JM, Grabińska KA, Muona M, et al.
    Am J Hum Genet, 2021 04 01;108(4):722-738.
    PMID: 33798445 DOI: 10.1016/j.ajhg.2021.03.013
    Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.
    Matched MeSH terms: Introns/genetics
  20. Zhou Q, Cheung YB, Jada SR, Lim WT, Kuo WL, Gray JW, et al.
    Cancer Biol. Ther., 2006 Nov;5(11):1445-9.
    PMID: 17102595
    AIM: The purpose of this study was to test the hypothesis if longer CA dinucleotide repeats are more common in the Asian population and also to gain insights into the interplay between the CA dinucleotide repeats and the frequencies of EGFR gene expression and amplifications as this might have therapeutic implications with regards to treatment with tyrosine kinase inhibitors.

    MATERIALS AND METHODS: The EGFR intron 1 polymorphism was analysed in three distinct healthy Asian subjects, namely, Chinese (N = 96), Malays (N = 98) and Indians (N = 100). Comparative genomic hybridisation was performed to investigate for changes in DNA copy number in relation to the polymorphic CA dinucleotide repeats in breast tumor tissues (N = 22).

    RESULTS: The frequency of short alleles with 14 and 15 CA repeats were most common in the Asian populations and significantly higher than those reported for Caucasians. The frequency of 20 CA repeats was 5%, almost 13-fold lower than previous reports. EGFR amplifications were detected in 23% and 11% of breast tumor tissues harboring short and long CA repeats, respectively.

    CONCLUSION: Our results show that the frequency of alleles encoding for short CA dinucleotide repeats is common in Asian populations. EGFR expression and amplification levels were also higher in Asian breast tumor tissues with short CA dinucleotide repeats. These findings suggest that the EGFR intron 1 polymorphism may influence response to treatment with tyrosine kinase inhibitors in breast cancer patients and further studies are warranted.

    Matched MeSH terms: Introns*
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