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PubMed2004

Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells.

Majority of anaplastic large-cell lymphomas (ALCLs) are associated with the t(2;5)(p23;q35) translocation, fusing the NPM (nucleophosmin) and ALK (anaplastic lymphoma kinase) genes (NPM-ALK). Recent studies demonstrated that ALK may also be involved in variant translocations, namely, t(1;2)(q25;p23), t(2;3)(p23;q21), t(2;17)(p23;q23) and inv(2)(p23q35), which create the TPM3-ALK, TFG-ALK5, CLTC-ALK, and ATIC-ALK fusion genes, respectively. Although overexpression of NPM-ALK has previously been shown to transform fibroblasts, the transforming potential of variant X-ALK proteins has not been precisely investigated. We stably transfected the cDNAs coding for NPM-ALK, TPM3-ALK, TFG-ALK, CLTC-ALK or ATIC-ALK into nonmalignant NIH3T3 cells. All X-ALK variants are tyrosine phosphorylated and their subcellular distribution was in agreement with that observed in tumors. Moreover, our results show that the in vitro transforming capacity of NIH3T3-transfected cells are in relation to the level of X-ALK fusion proteins excepted for TPM3-ALK for which there is an inverse correlation. The differences between the five X-ALK variants with regard to proliferation rate, colony formation in soft agar, invasion, migration through the endothelial barrier and tumorigenicity seem to be due to differential activation of various signaling pathways such as PI3-kinase/AKT. These findings may have clinical implications in the pathogenesis and prognosis of ALK-positive ALCLs.

Anaplastic Lymphoma Kinase↗

PubMed2005

Genetic polymorphism of CYP2C8 in three Malaysian ethnics: CYP2C82 and CYP2C83 are found in Malaysian Indians.

BACKGROUND: CYP2C8 is genetically polymorphic. Four variants, CYP2C8*2, CYP2C8*3, CYP2C8*4 and CYP2C8*5, which contain mutations in the coding regions have been reported to exhibit different enzyme activity as compared with CYP2C8*1. OBJECTIVE: To determine the allele frequency of three codon-changing variants (CYP2C8*2, CYP2C8*3 and CYP2C8*4) in the Malaysian population. METHOD: Healthy unrelated volunteers from three major races in Malaysia were recruited. The study was approved by the local Research Ethics Committee. DNA was extracted using a standard protocol. A two-step multiplex PCR method was developed to detect three alleles of CYP2C8. PCR results were confirmed by subsequent direct DNA sequencing. RESULT: Only the Indians showed CYP2C8 polymorphism with allele frequency of 98% for CYP2C8*1, 0.8% for CYP2C8*2 and 1.2% for CYP2C8*3. CYP2C8*4 was not detected in any of the ethnic groups. CONCLUSION: To the best of our knowledge, the current study described, for the first time polymorphisms of CYP2C8 in Malaysian Indians.

Alleles↗

PubMed1998

Detection of mutations in the apolipoprotein CII gene by denaturing gradient gel electrophoresis. Identification of the splice site variant apolipoprotein CII-Hamburg in a patient with severe hypertriglyceridemia.

Familial apolipoprotein (apo) CII deficiency is a rare autosomal recessive inborn error of metabolism clinically resembling lipoprotein lipase deficiency. A number of mutations of the apo CII gene are known to date; they are located in the promoter region, the coding exons, or in the splice junctions. We present a simple assay based on PCR and denaturing gradient gel electrophoresis, which allows scanning of the promoter, the entire coding sequence, and the splice junctions of the apo CII gene for sequence variants. All gene fragments are amplified using a common PCR protocol and are examined for mutations on a single gradient gel. Using this method and direct sequencing, we identified homozygosity for a donor splice-site mutation in the second intron, previously designated apo CII-Hamburg, as the genetic cause of apo CII deficiency in a 9-year-old boy presenting with chylomicronemia, eruptive xanthoma, and pancreatitis. In addition, the method allowed us to detect all of six different other known mutations of the apo CII gene. We conclude, therefore, that our assay is highly sensitive; in addition, it is easy to perform and may facilitate the differential diagnosis of disorders of lipoprotein metabolism at the genetic level.

Alternative Splicing↗

PubMed1984

A minor class of 5S rRNA genes in Saccharomyces cerevisiae X2180-1B, one member of which lies adjacent to a Ty transposable element.

In Saccharomyces cerevisiae the majority of the genes for 5S rRNA lie within a 9kb rDNA sequence that is present as 100-200 tandemly-repeated copies on Chromosome XII. Following our observations that about 10% of yeast 5S rRNA exists as minor variant sequences, we screened a collection of yeast DNA fragments cloned in lambda gt for 5S rRNA genes whose flanking sequences differed from those adjacent to 5S rRNA genes of the rDNA repeat. Three variant 5S rRNA genes were isolated on the basis of such dissimilarity to rDNA repeat sequences. They display a remarkable conservation of their DNA in the vicinity of the 5S coding region, and are examples of a minor form of 5S rRNA coding sequence present in a small number of copies in the yeast genome. These variant sequences appear to be transcribed as efficiently as 5S rRNA genes of the rDNA repeat. In one of our isolates of the variant sequence a Ty transposable element is inserted 145bp upstream of the initiation point for 5S rRNA synthesis.

Base Sequence↗

PubMed2004

An investigation of mammographic density and gene variants in healthy women.

This cross-sectional study examined if polymorphisms in genes that code for enzymes involved in the production and metabolism of estrogens are associated with mammographic density, a strong predictor of breast cancer risk. The study included 328 healthy women of different ethnicities who underwent mammographic screening and donated a blood or mouthwash sample for DNA analysis. After digitizing cranio-caudal views of the mammograms, we performed computer-assisted mammographic density assessment. Following DNA extraction, samples were analyzed for polymorphisms in the COMT (Val158Met), CYP1A1 (Ile462Val), CYP1B1 (Val432Leu), CYP1A2 (*1F) and CYP17 (T27C) genes using PCR-RFLP. Breast density was lower in Caucasians than in Asians. Caucasian women were less likely to carry the CYP1A1 variant allele and more likely to carry the variant alleles for CYP1B1 and COMT than women with Asian or Hawaiian ancestry. The low-activity COMT and CYP1A2 variant alleles were weakly related to lower percent mammographic density after adjustment for age, ethnicity, body mass index and reproductive variables (p for gene-dosage =0.08 and 0.05, respectively). These relations were observed in premenopausal women only and were similar in direction and magnitude after stratification by ethnicity. We found no significant associations between breast density and the variant alleles for CYP1A1, CYP1B1 and CYP17. Our data suggest lower mammographic density for women carrying the COMT and CYP1A2 variant alleles than for women carrying the common alleles, though this is the opposite of what is commonly hypothesized from the enzyme function.

Adult↗

PubMed1990

A herpes simplex virus type 1 recombinant with both copies of the Vmw175 coding sequences replaced by the homologous varicella-zoster virus open reading frame.

Varicella-zoster virus (VZV) gene 62 encodes a protein with a predicted Mr of 140,000 (VZV 140K) that shares considerable amino acid homology with the immediate early (IE) regulatory protein Vmw175 of herpes simplex virus type 1 (HSV-1) and is believed to be its functional equivalent. We have tested this hypothesis by insertion of VZV gene 62 (expressed from the HSV-1 IE3 promoter) into both IE3 gene loci in the short region repeats of the HSV-1 genome. The parent virus used for this manipulation was D30EBA, which is a variant of HSV-1 from which the majority of the Vmw175 coding sequences have been deleted. Like other HSV-1 viruses lacking Vmw175 functions, D30EBA is able to grow only in cell lines which express Vmw175 constitutively. The resulting recombinant virus. HSV-140, is able to propagate (but unable to form obvious plaques) on normal cell lines. The properties of HSV-140 were studied by monitoring the time course of polypeptide expression and DNA replication during normal infection. We found that at high multiplicity HSV-140 synthesized apparently normal amounts of many viral polypeptides but that the expression of certain late genes was reduced; this slight defect may be related to less efficient DNA replication by HSV-140. At low multiplicity HSV-140 expressed viral proteins inefficiently. Surprisingly, VZV 140K was produced in large amounts at later times of a normal infection, indicating that the polypeptide fails to autoregulate the IE3 promoter. The results strongly suggest that VZV 140K is able to perform most of the functions of Vmw175 during growth of HSV-1, but that differences in detail lead to less efficient virus growth.

Animals↗

PubMedDate not supplied

Apparent monomorphism of ALDH2 in seven American Indian populations.

Deficiency of mitochondrial aldehyde dehydrogenase (ALDH2) has been previously reported in South American Indians. We therefore assayed five individuals from each of five South American Indian populations (Quechua, Karitiana, Ticuna, Surui, Guahiba), and two North American populations (Maya and Moskoke) for the presence of the Oriental ALDH2(2) variant. These samples were also surveyed for other alleles altering ALDH2 function. Allele-specific amplification assay (ASA) did not detect the ALDH2(2) allele in any of the New World populations studied. The entire coding sequence of the ALDH2 cDNA was enzymatically amplified in partially overlapping fragments. Each fragment was digested using restriction endonucleases and subfragments 148-285 b.p. in length were analyzed by the single-stranded conformation polymorphism (SSCP) technique. No variants were detected within the coding region of the ALDH2 gene in any of the seven American Indian populations. Three potentially correct explanations for these results are suggested. First, an ALDH2 polymorphism is present but undetectable by SSCP; second, none of the studied individuals were ALDH2 negative; third, the polymorphism occurs beyond the coding region of ALDH2 gene.

Aldehyde Dehydrogenase↗

PubMed1994

A monocistronic transcript for a trypanosome variant surface glycoprotein.

Many protein-encoding genes of African trypanosomes are transcribed as large polycistronic pre-mRNAs that are processed into individual mRNAs containing a 5' spliced leader and 3' poly(A). The 45- to 60-kb pre-mRNAs encoding some variant surface glycoproteins (VSGs) contain as many as eight unrelated coding regions. Here we identify the promoter for a metacyclic VSG gene that is expressed without duplication in a bloodstream trypanosome clone. This 70-bp promoter is located 2 kb upstream of the telomere-linked VSG gene and directs the synthesis of a monocistronic VSG pre-mRNA lacking the 5' spliced leader. Its sequence only slightly resembles those of other known trypanosome promoters, but it does cross-hybridize with several related sequences elsewhere in the genome. These results suggest that a new class of trypanosome promoters has been found, whose function is to initiate monocistronic transcription of those VSG genes normally expressed during the metacyclic stage.

Amino Acid Sequence↗

PubMed1996

Suppression of prostaglandin E receptor signaling by the variant form of EP1 subtype.

A cDNA clone of prostaglandin (PG) E receptor EP1 subtype (rEP1) was isolated from a rat uterus cDNA library. It encodes 405 amino acid residues with seven transmembrane-spanning domains and couples to Ca2+ mobilization. In addition, three cDNA clones encoding a variant form of rEP1 were isolated. The open reading frame can code a 366-amino acid protein carrying a specific change of 49 amino acids from the middle of transmembrane segment VI to COOH terminus; it possesses a transmembrane segment VII-like structure lacking an intracellular COOH-terminal tail. Southern blot analysis of rat genomic DNA and genomic polymerase chain reaction demonstrated that these cDNAs were derived from a single copy gene. Northern blot analysis and ribonuclease protection assay revealed that both rEP1 and rEP1-variant receptor mRNAs were highly expressed in the kidney. Immunoblot with an antibody directed toward the specific region of rEP1-variant receptor showed that rEP1-variant receptor protein was expressed in the membrane of the kidney and Chinese hamster ovary (CHO) cells transfected with rEP1-variant cDNA. Thus, the rEP1-variant receptor is translated from mRNA which is not spliced at nucleotide position 952 in the segment VI transmembrane region. rEP1-variant receptor retained the ligand binding activity with affinity and specificity similar to rEP1 receptor, but lost the coupling of signal transduction systems by itself. However, when rEP1-variant receptor was stably co-expressed with rEP1 receptor in CHO cells, the Ca2+ mobilization mediated by EP1 receptor was significantly suppressed. Furthermore, when rEP1-variant receptor was expressed in CHO cells, cAMP formation by activation of endogenous EP4 receptor was strongly blocked. These results suggest that the rEP1-variant receptor may affect the efficiency of signal coupling of PGE receptors and attenuate the action of PGE2 on tissues.

Amino Acid Sequence↗

PubMed2000

Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms.

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting 1/10,000-15,000 girls. The disease-causing gene was identified as MECP2 on chromosome Xq28, and mutations have been found in approximately 80% of patients diagnosed with RTT. Numerous mutations have been identified in de novo and rare familial cases, and they occur primarily in the methyl-CpG-binding and transcriptional-repression domains of MeCP2. Our first diagnostic strategy used bidirectional sequencing of the entire MECP2 coding region. Subsequently, we implemented a two-tiered strategy that used denaturing high-performance liquid chromatography (DHPLC) for initial screening of nucleotide variants, followed by confirmatory sequencing analysis. If a definite mutation was not identified, then the entire MECP2 coding region was sequenced, to reduce the risk of false negatives. Collectively, we tested 228 unrelated female patients with a diagnosis of possible (209) or classic (19) RTT and found MECP2 mutations in 83 (40%) of 209 and 16 (84%) of 19 of the patients, respectively. Thirty-two different mutations were identified (8 missense, 9 nonsense, 1 splice site, and 14 frameshifts), of which 12 are novel and 9 recurrent in unrelated patients. Seven unclassified variants and eight polymorphisms were detected in 228 probands. Interestingly, we found that T203M, previously reported as a missense mutation in an autistic patient, is actually a benign polymorphism, according to parental analysis performed in a second case identified in this study. These findings highlight the complexities of missense variant interpretation and emphasize the importance of parental DNA analysis for establishing an etiologic relation between a possible mutation and disease. Overall, we found a 98.8% concordance rate between DHPLC and sequence analyses. One mutation initially missed by the DHPLC screening was identified by sequencing. Modified conditions subsequently enabled its detection, underscoring the need for multiple optimized conditions for DHPLC analysis. We conclude that this two-tiered approach provides a sensitive, robust, and efficient strategy for RTT molecular diagnosis.

Alleles↗

PubMed2001

Cloning and characterization of the mouse polyamine-modulated factor-1 (mPMF-1) gene: an alternatively spliced homologue of the human transcription factor.

The natural polyamines and their analogues have been implicated in transcriptional regulation of specific genes. Human polyamine-modulated factor-1 (hPMF-1) was the first polyamine-responsive transcription factor identified. Here the mouse homologue of the hPMF-1 gene is described. Interestingly, the mouse gene (mPMF-1) codes for two alternatively spliced mRNAs. Both of the mouse splice variants, mPMF-1S and mPMF-1L, possess C-terminal coiled-coil domains nearly identical to that found in hPMF-1 and are highly homologous with the human protein. The C-terminal coiled-coil structure is necessary for transcriptional activation. However, the shorter protein, mPMF-1S, does not contain an N-terminal coiled-coil region as do both hPMF-1 and the longer mPMF-1L. mPMF-1L mRNA codes for a protein of 202 amino acids, 37 amino acids longer than the human protein. By contrast, mPMF-1S codes for only 133 amino acids, as a result of two exons being omitted compared with mPMF-1L. Both mouse transcription factors can interact with Nrf-2 (nuclear factor-E2-related factor 2), the normal partner of hPMF-1, substantiating the importance of the C-terminal coiled-coil region responsible for this interaction. Finally, the expression of mPMF-1 is induced when mouse M1 myeloid leukaemia cells are exposed to polyamine analogues, suggesting control similar to that observed for the hPMF-1.

Alternative Splicing↗

PubMed1992

Genetic mechanisms of antigenic variation in infectious bursal disease virus: analysis of a naturally occurring variant virus.

The major immunogenic protein VP2 from a pathogenic field isolate (variant A virus) of infectious bursal disease virus (IBDV) was cloned and sequenced to examine antigenic variations. The VP2 open reading frame consists of 1509 nucleotides and codes for a 503 amino acid protein. Overall, the VP2 amino acid sequence of the variant A virus shares 98.6% identity with VP2 genes from other published IBDV strains. However, within the central region of VP2 (amino acids 222-334) lies a highly divergent area that we have termed the variable domain. Relative to five other IBDV isolates, a total of six amino acid changes occur within the variable domain of the variant A virus. At positions 284-288, a substitution of isoleucine to threonine, a decrease in the number of Chou and Fasman beta turns, and a switch from a hydrophilic to a hydrophobic region are found only in the variant A virus. Together these changes predict a decrease in antigenicity as determined by calculation of potential antigenic sites. This suggests that only minor changes within VP2 contributed to the emergence of a variant virus that can cause disease in immunized birds.

Amino Acid Sequence↗

PubMed1996

Dopamine D3 receptor gene: organization, transcript variants, and polymorphism associated with schizophrenia.

DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D3 receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR-based method was developed for genotyping this polymorphism. The distribution of the Msp I and Bal I genotypes were not independent in 297 individuals (chi 2 = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism (chi 2 = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM-III-R chronic schizophrenics and 85 controls (chi 2 = 5.3, df = 1, P = 0.02) and found more important in mal than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls (chi 2 = 0.06, df = 1, P = 0.80, chi 2 = 0.22, df = 1, P = 0.90 and chi 2 = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3' part of the gene may explain the discrepant results obtained with the two polymorphisms.

Animals↗

PubMed1985

Changes in the levels of three different classes of histone mRNA during murine erythroleukemia cell differentiation.

We used a gene-specific S1 nuclease assay to study the changes in steady-state mRNA levels of several core histone variants during the differentiation of murine erythroleukemia cells. These studies allowed us to distinguish three distinct expression classes of histone genes. The expression of the major replication-dependent class of histone genes was tightly linked to DNA synthesis. The concentrations of these transcripts decreased rapidly as cell division slowed during the process of differentiation. In contrast, the replication-independent H3.3 transcript levels were constitutively maintained throughout differentiation and were unaffected by inhibitors of DNA or protein synthesis. We also identified among the cloned histone genes used as probes a third expression class, the partially replication-dependent variants. Expression of these transcripts became transiently uncoupled from the reduced rate of DNA synthesis accompanying the early stages of differentiation. We show that their synthesis is sensitive to the DNA synthesis inhibitor hydroxyurea but that selective uncoupling from DNA synthesis of these histone mRNAs occurs at a specific stage of differentiation. We present several hypotheses to explain how this might be accomplished. The expression characteristics of the mRNAs studied coincided with those of the proteins for which they code, indicating that changes in the relative levels of the different variants is mediated at least in part by changes in mRNA levels.

Animals↗

PubMed1991

Impaired expression of glycogen synthase mRNA in skeletal muscle of NIDDM patients.

Based on recent studies of the abnormal physiology and biochemistry of the glycogen synthesis in skeletal muscle of non-insulin-dependent diabetes mellitus (NIDDM) patients and their first-degree relatives, the key enzyme of this pathway, glycogen synthase (GS), is considered a candidate gene in the pathogenesis of insulin resistance. Comparing matched groups of 14 NIDDM patients with 14 control subjects, we found that impaired insulin-stimulated nonoxidative glucose metabolism of peripheral tissue (P less than 0.02) and reduced total GS activity (P less than 0.05) of vastus lateralis muscle from patients with NIDDM were accompanied by a 39% reduction (P less than 0.02) in the steady state level of GS mRNA per microgram DNA of muscle. In both diabetic and control subjects, the mRNA expression of GS was unaffected after euglycemic-hyperinsulinemic clamp for 4 h. With single-stranded conformation polymorphism analysis of the entire coding sequence of the GS gene, we were unable to detect any genetic variants in a subset of eight NIDDM patients. We conclude that abnormal pretranslational regulation of the GS gene may contribute to impaired glycogen synthesis of muscle in NIDDM. Our studies give no evidence for structural changes in the coding region of the GS gene, and it is unknown if the decreased mRNA expression is due to impaired transcription or accelerated degradation of the transcript.

Blotting, Northern↗

PubMed2004

A new family of "H3L-like" histone genes.

The H3L histone variant gene in Paracentrotus lividus (sea urchin) shows almost all typical features of the replication-dependent histone genes, but it codes for the H3.3 histone protein with the S.//. A.IG amino acid motif, which is typical of the variants synthesized in a replication-independent manner. "H3L-like" histone genes have been found in several unrelated organisms. These genes are intronless and encode for the typical H3.3 histone proteins. The newly described family of H3L-like variants, nearly ubiquitous within the animal kingdom, could represent the common ancestor of H3 and H3.3 histone genes.

Amino Acid Sequence↗

PubMed1997

Nucleotide deletion and P addition in V(D)J recombination: a determinant role of the coding-end sequence.

During V(D)J recombination, the coding ends to be joined are extensively modified. Those modifications, termed coding-end processing, consist of removal and addition of various numbers of nucleotides. We previously showed in vivo that coding-end processing is specific for each coding end, suggesting that specific motifs in a coding-end sequence influence nucleotide deletion and P-region formation. In this study, we created a panel of recombination substrates containing actual immunoglobulin and T-cell receptor coding-end sequences and dissected the role of each motif by comparing its processing pattern with those of variants containing minimal nucleotide changes from the original sequence. Our results demonstrate the determinant role of specific sequence motifs on coding-end processing and also the importance of the context in which they are found. We show that minimal nucleotide changes in key positions of a coding-end sequence can result in dramatic changes in the processing pattern. We propose that each coding-end sequence dictates a unique hairpin structure, the result of a particular energy conformation between nucleotides organizing the loop and the stem, and that the interplay between this structure and specific sequence motifs influences the frequency and location of nicks which open the coding-end hairpin. These findings indicate that the sequences of the coding ends determine their own processing and have a profound impact on the development of the primary B- and T-cell repertoires.

Animals↗

PubMed2006

Paraoxonase polymorphisms, haplotypes, and enzyme activity in Latino mothers and newborns.

Recent studies have demonstrated widespread pesticide exposures in pregnant women and in children. Plasma paraoxonase 1 (PON1) plays an important role in detoxification of various organophosphates. The goals of this study were to examine in the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort of Latina mothers and their newborns living in the Salinas Valley, California, the frequencies of five PON1 polymorphisms in the coding region (192QR and 55LM) and the promoter region (-162AG, -909CG, and -108CT) and to determine their associations with PON1 plasma levels [phenylacetate arylesterase (AREase) ] and enzyme activities of paraoxonase (POase) and chlorpyrifos oxonase (CPOase) . Additionally, we report results of PON1 linkage analysis and estimate the predictive value of haplotypes for PON1 plasma levels. We found that PON1-909, PON1-108, and PON1(192) had an equal frequency (0.5) of both alleles, whereas PON1-162 and PON1(55) had lower variant allele frequencies (0.2) . Nearly complete linkage disequilibrium was observed among coding and promoter polymorphisms (p < 0.001) , except PON1(192) and PON1-162 (p > 0.4) . Children's PON1 plasma levels (AREase ranged from 4.3 to 110.7 U/mL) were 4-fold lower than their mothers' (19.8 to 281.4 U/mL) . POase and CPOase activities were approximately 3-fold lower in newborns than in mothers. The genetic contribution to PON1 enzyme variability was higher in newborns (R2 = 25.1% by genotype and 26.3% by haplotype) than in mothers (R2 = 8.1 and 8.8%, respectively) . However, haplotypes and genotypes were comparable in predicting PON1 plasma levels in mothers and newborns. Most of the newborn children and some pregnant women in this Latino cohort may have elevated susceptibility to organophosphate toxicity because of their PON1192 genotype and low PON1 plasma levels.

Adolescent↗