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At least 235 records · Page 13Linked to original sources
PubMed2002

Identification of polymorphisms in the human SHP1 gene.

Because mutations in human SHP1 underlie obesity and diabetes, SHP1 is a candidate gene for human lipodystrophy syndromes. To identify possible disease mutations and/or common single-nucleotide polymorphisms (SNPs), we developed primer pairs to amplify the promoter and coding region of SHP1. We used these pairs to sequence SHP1 in lipodystrophy patients who had no mutations in known lipodystrophy genes, and also in normal control subjects. We found no rare SHP1 coding sequence variants that were exclusive to patients with lipodystrophy. However, we found four polymorphisms, namely, an SNP [-394]C>T in the promoter, a micro-deletion polymorphism [-195]delCTGA in the promoter, a missense SNP 541G>C in exon 1 (which changed the amino acid sequence G171A), and an SNP 903C>T in exon 2. The findings suggest that SHP1 mutations are not commonly seen in patients with lipodystrophy who had no mutations in known disease genes. However, the identification of amplification primers and polymorphisms provides tools to further investigate SHP1 for association with other phenotypes.

Gene Frequency↗
PubMed2003

Manual 768 or 384 well microplate gel 'dry' electrophoresis for PCR checking and SNP genotyping.

Electrophoresis continues to be a mainstay in molecular genetic laboratories for checking, sizing and separating both PCR products, nucleic acids derived from in vivo or in vitro sources and nucleic acid-protein complexes. Many genomic and genetic applications demand high throughput, such as the checking of amplification products from many loci, from many clones, from many cell lines or from many individuals at once. These applications include microarray resource development and expression analysis, genome mapping, library and DNA bank screening, mutagenesis experiments and single nucleotide polymorphism (SNP) genotyping. PCR hardware compatible with industry standard 96 and 384 well microplates is commonplace. We have previously described a simple system for submerged horizontal 96 and 192 well polyacrylamide or agarose microplate array diagonal gel electrophoresis (MADGE) which is microplate compatible and suitable for PCR checking, SNP typing (restriction fragment length polymorphism or amplification refractory mutation system), microsatellite sizing and identification of unknown mutations. By substantial redesign of format and operations, we have derived an efficient 'dry' gel system that enables direct 96 pin manual transfer from PCR or other reactions in microplates, into 768 or 384 well gels. Combined with direct electrode contact in clamshell electrophoresis boxes which plug directly to contacts in a powered stacking frame and using 5-10 min electrophoresis times, it would be possible (given a sufficient supply of PCRs for examination) for 1 million gel tracks to be run per day for a minimal hardware investment and at minimal reagent costs. Applications of this system for PCR checking and SNP genotyping are illustrated.

DNA↗
PubMedDate not supplied

Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers.

Polymorphisms in the mu-opioid receptor gene (OPRM1) are primary candidate sources of clinical variability in opioid therapy. Apart from the 118A>G single nucleotide polymorphism, nothing is known about the role of OPRM1 mutations in opioid therapy. The influence of the OPRM1 mutations on opioid pharmacodynamics was assessed in pooled data from 31 healthy volunteers obtained in previous studies with available plasma concentrations and pupil diameters after intravenous administration of morphine or morphine-6-glucuronide (M6G). A total of 24 candidate ORPM1 mutations were screened for and those found at an allelic frequency of at least 5% in the 31 subjects were analyzed for functional consequences, using population pharmacokinetic-pharmacodynamic modeling of the miotic effects of the opioids as a reliable and sensitive surrogate parameter of the central nervous opioid effects. Polymorphisms at an allelic frequency of > or =5% (n=310) were 118A>G in exon 1 (11.5%), the IVS2-31G>A (8.9%) and IVS2-691C>G (44.5%) SNPs in intron 2. The 118A>G SNP significantly increased the values of EC50 by a factor of more than 2 (non-mutated: EC50,morphine=30 nmol/l, EC50,M6G=750 nmol/l, 118G carriers: EC50,morphine=66 nmol/l, EC50,M6G=1650 nmol/l), whereas the IVS2-691C>G SNP had no effect. Based on morphine and M6G, the present analysis encourages focusing on the 118A>G SNP when investigating the role of OPRM1 mutations for the activity of opioid analgesics. Other OPRM1 mutations are probably less important either owing to low allelic frequency or due to poor indications for functional consequences. This applies to opioid potency in the context of opioid therapy but not to pain processing or substance addiction, in which opioid receptors are involved but other or additional OPRM1 mutations may be important.

Alleles↗
PubMedDate not supplied

Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies.

BACKGROUND: Membranous glomerulonephritis is an immune-mediated disease. In a recent case of antenatal membranous glomerulonephritis, we identified neutral endopeptidase (NEP) as the podocyte target antigen of circulating antibodies produced by the mother who failed to express NEP on granulocytes. We aimed to investigate whether the disease could affect other families, to search for mutations in the metallomembrane endopeptidase (MME) gene for NEP, and to analyse the outcome of the antenatal renal insult. METHODS: From three families with a case of neonatal membranous glomerulopathy, we detected mutations by direct sequencing of genomic PCR products. Single nucleotide polymorphism (SNP) analysis was undertaken with five SNPs located in the MME gene. IgG subclasses with anti-NEP activity were determined by western blotting. FINDINGS: In five mothers, we identified two compound heterozygous or homozygous mutations in the MME gene. The first, a 1342C-->T nonsense mutation, was detected in one family. The second, 446delC, was detected in all three families; all chromosomes bearing this mutation had the same alleles for the five SNPs. Severity of neonatal renal disease was determined by the mothers' IgG response to fetal NEP antigens expressed on glomerular podocytes. The oldest affected individual, now aged 20 years, has developed severe chronic renal failure. INTERPRETATION: Truncating mutations in the MME gene are the cause of alloimmunisation during pregnancy. Idiopathic renal failure in early adulthood might be caused by immune-mediated fetal nephron loss. We show that disease caused by fetomaternal alloimmunisation secondary to a genetic defect is not restricted to blood cells. RELEVANCE TO CLINICAL PRACTICE: During pregnancy, the absence of the NEP protein induces an alloimmunisation process against NEP presented by fetal cells, including syncytiotrophoblasts. The fetal podocyte insult and ensuing nephron loss could lead to chronic renal failure in early adulthood. Alloimmunisation against NEP should be considered as a leading cause of membranous glomerulopathy early in life. Concentrations of circulating anti-NEP antibodies should be carefully monitored during subsequent pregnancies, and specific therapeutic approaches developed. This new disease might also account for idiopathic chronic renal failure detected during adolescence, in individuals who can be identified by searching for anti-NEP antibodies in their mother and by MME gene mutation analysis. NEP deficiency should also be considered in patients developing de-novo membranous glomerulopathy after renal transplantation.

Adult↗
PubMed2006

Evidence for association of SLC7A9 gene haplotypes with cystinuria manifestation in SLC7A9 mutation carriers.

Cystinuria is a complex genetic disorder. In the present study, we report on the strict linkage disequilibrium of SLC7A9 mutations with the wild type SLC7A9 haplotype of 15 single nucleotide polymorphisms (SNPs) and their effect on cystinuria manifestation and classification. Specifically, screening for mutations and polymorphisms was performed in the family members of ten cystinuric patients with SLC7A9 gene mutations. The molecular genetic and clinical data of cystinuric patients and their relatives were combined to construct the SLC7A9 SNP haplotypes and evaluate the manifestation of the disorder in carriers for a SLC7A9 gene mutation. It was found that all carriers of a SLC7A9 mutation manifested cystinuria if their normal allele had non-wild type nucleotides in two or more of the identified polymorphic sites. Subsequently, the polymorphic background of the SLC7A9 gene probably affects the expression of the disorder in SLC7A9 mutation carriers and points to a revised genetic classification of cystinuric patients.

Amino Acid Transport Systems, Basic↗
PubMed2003

Evaluation and understanding of myocilin mutations in Indian primary open angle glaucoma patients.

PURPOSE: To screen for mutations in the MYOC gene of patients with Primary Open Angle Glaucoma (POAG) in India and to better understand the mutations using a possible model of myocilin. METHODS: We analyzed DNA for mutations in 107 subjects with POAG and 90 normal control subjects. The exonic sequences of the MYOC gene from all subjects were amplified by Polymerase Chain Reaction (PCR). We carried out Single Strand Conformation Polymorphism (SSCP) for all the PCR products. The DNA samples which showed mobility shift in the banding pattern in SSCP gel were sequenced. We also analyzed the presence of the common mutation Gln368Stop using a specific restriction enzyme Taa 1. The mutations observed here and elsewhere have been mapped onto a possible model built for myocilin using a knowledge-based consensus modeling approach. RESULTS: Two heterozygous mutations Gly367Arg (1099G>A) and Thr377Met (1130C>T) were identified in exon3 of the MYOC gene of probands 40-1 and 51-1 respectively, from material obtained from the 107 unrelated subjects with POAG. These two mutations were not present in the normal controls studied. We identified a Single Nucleotide Polymorphism (SNP) Gly122Gly (366C>T) in exon1 of proband 57-1 as a non-disease causing variation. The common mutation Gln368Stop found in the Western population was not observed in the POAG cases screened in Indian population. The possible structural model for myocilin suggests a predominantly [beta]-strand rich C-terminal region (181-504) which is connected by the [alpha]-helical mid-region (111-180) to the N-terminal region (34-110) which has low secondary structure content. Both the mutations, Gly367Arg and Thr377Met identified in our study, map on to the C-terminal region. These mutations disfavor burial of this region during oligomer formation due to the charged or bulky nature of the mutants. Most of the other mutations known for myocilin also are surface exposed on the C-terminal region. CONCLUSIONS: Our findings indicate that the mutation frequency of the MYOC gene is 2% in the Indian population affected with POAG, which is not a well-studied ethnic group of the Asian continent. The variations identified in our study have been previously reported in the Western population. The nonsense mutation Gln368Stop was not observed in the present study and thereby suggests that it may not be a common disease-causing mutation in the Indian population. Amongst other Asian populations, studies in Japan also didn't report this nonsense mutation. The location of these mutations suggest that a plausible mode of action could be by disruption of dimer or oligomer formation by the C-terminal region allowing greater chances of nucleation of aggregation by the N-terminal region.

Adolescent↗
PubMed2000

The voltage-gated sodium channel beta2-subunit gene and idiopathic generalized epilepsy.

Recent identification of ion channel gene mutations in Mendelian epilepsies suggests that genetically driven neuronal hyperexcitability plays an important role in epileptogenesis. In this study, we tested the hypothesis that genetic variation in the human SCN2B gene confers liability to common subtypes of idiopathic generalized epilepsies (IGE). A systematic search for mutations was performed in 92 IGE patients. We detected a novel single nucleotide polymorphism (SNP), however, allele frequencies did not differ between IGE patients and controls (chi2 = 0.19, df = 1, p = 0.744). Furthermore, a missense mutation in codon 209 (Asn209Pro) was identified in one patient, but was found to be absent in an affected sibling of the index patient. Thus, our results do not suggest a major role of the SCN2B gene in the etiology of common IGE subtypes.

Adult↗
PubMed2003

Prenatal diagnosis of factor X deficiency using a combination of direct mutation detection and linkage analysis with an intragenic single nucleotide polymorphism.

OBJECTIVE: To present a family in which it was possible to perform prenatal diagnosis for recessively inherited factor X deficiency using both direct mutation detection as well as linkage analysis. METHODS: In a family where both parents were known to be carriers of factor X deficiency, fetal DNA was obtained from an ongoing pregnancy by CVS in the first trimester. Direct DNA sequencing was used to detect a previously identified factor X mutation, and linkage analysis using a single nucleotide polymorphism (SNP) was used to follow the segregation of the other parent's factor X alleles. RESULTS: Our studies predicted the fetus in question to be a heterozygote carrier of factor X deficiency, and this was demonstrated to be correct at birth. CONCLUSIONS: This is the first reported case of prenatal diagnosis of factor X deficiency. In addition, this case demonstrates the remarkable utility of SNPs in linkage analysis of rare genetic disorders.

Adult↗
PubMed2006

Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism.

The extensive genetic heterogeneity of Bardet-Biedl syndrome (BBS) is documented by the identification, by classical linkage analysis complemented recently by comparative genomic approaches, of nine genes (BBS1-9) that account cumulatively for about 50% of patients. The BBS genes appear implicated in cilia and basal body assembly or function. In order to find new BBS genes, we performed SNP homozygosity mapping analysis in an extended consanguineous family living in a small Lebanese village. This uncovered an unexpectedly complex pattern of mutations, and led us to identify a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above BBS10 mutation and another one in the same gene. Although triallelism (three deleterious alleles in the same patient) has been described in some BBS families, we have to date no evidence that this is the case in the present family. The analysis of this family challenged linkage analysis based on the expectation of a single locus and mutation. The very high informativeness of SNP arrays was instrumental in elucidating this case, which illustrates possible pitfalls of homozygosity mapping in extended families, and that can be explained by the rather high prevalence of heterozygous carriers of BBS mutations (estimated at one in 50 in Europeans).

Adolescent↗
PubMed2004

DNA analysis by MALDI-TOF mass spectrometry.

The last decade has seen an increased demand for high-throughput DNA analysis. This is mainly due to the human genome sequencing project that is now completed. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was pinpointed early on as a technology that could be of great use for sequence variation analysis in the post-genome sequencing era. Applications developed first on this platform were for SNP genotyping. Several strategies for allele-discrimination (hybridization, cleavage, ligation, and primer extension) were combined with MALDI-TOF mass spectrometric detection. Nowadays, in practice, only primer extension methods are applied for large-scale SNP genotyping studies with MALDI-TOF detection. Problems surrounding the integration of SNP genotyping by MALDI-TOF mass spectrometry at high throughput are largely mastered now. Mass spectrometry geared presentations at the HUGO Mutation Detection Meeting in Palm Cove, Australia almost exclusively focused on novel applications that go beyond standard SNP genotyping. These applications are more demanding in terms of chemistry and molecular biology. Molecular haplotyping, expression profiling, DNA methylation analysis, and mutation detection are now being demonstrated.

DNA Mutational Analysis↗
PubMed2000

Rapid genotyping of factor V Leiden mutation using single-tube bidirectional allele-specific amplification and automated ultrathin-layer agarose gel electrophoresis.

We report a novel, high-throughput genotyping method by single nucleotide polymorphism (SNP) analysis using bidirectional allele-specific amplification with polymerase chain reaction (PCR) in a single-step/single-tube format. Blood coagulation factor V G1691A (also referred to as Leiden) mutation was chosen as a model system for SNP detection, as this is one of the most common inherited risk factors of thrombosis, effecting 2-5% of the human population. The rationale of our method is the production of allele-specific PCR fragments, different in size, which was achieved by bidirectional amplification, starting from the position of the mutation. Thus, both homozygosity and heterozygosity were readily identified from a single reaction by simply determining the sizes of the resulting PCR products. The advantage of our assay, compared to other single-tube systems, is that this method did not require the use of pre-PCR labeled (fluorophore) primers or probes. Preferential production of the allele-specific products was achieved by a hot-start, time release PCR system. Specificity was increased by introducing a mismatch in the 3'-antepenultimate position of the allele-specific primers. This method made possible the large-scale screening for the factor V Leiden mutation using single-tube PCR followed by automated ultrathin-layer agarose gel electrophoresis, with real-time detection of the "in migratio" ethidium-bromide-labeled fragments.

Automation↗
PubMed2005

Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32.

The efficiency of the complement system as an innate immune defense mechanism depends on a fine control that restricts its action to pathogens and prevents non-specific damage to host tissues. Genetic and functional analyses have shown that this critical control of complement activation may be impaired in atypical hemolytic uremic syndrome (aHUS) patients. Mutations in HF1, MCP or FI have been found in aHUS patients, but incomplete penetrance of the disease in individuals carrying these mutations is relatively frequent and no genetic defect has yet been found in a majority of aHUS patients. We report here the identification of a specific SNP haplotype block, spanning the MCP gene in the regulators of complement activation gene cluster, which is over-represented in aHUS patients and strongly associates with the severity of the disease. Linkage disequilibrium analyses suggest that this SNP haplotype also includes the CR1, DAF and C4BP genes. Initial studies identified two SNPs in the haplotype that influence the transcription activity of the MCP promoter in transient transfection experiments. Notably, the SNP haplotype block was found to be particularly frequent among patients who carry mutations in HF1, MCP or FI. These findings and the identification of aHUS patients carrying mutations in two complement regulatory genes provide an important insight into the etiology of aHUS. Together, they suggest that complement regulatory molecules act as a protein network and that multiple hits, involving plasma- and membrane-associated complement regulatory proteins, are necessary to impair protection to host tissues and to confer significant predisposition to aHUS.

Antigens, CD↗
PubMed2004

Nitroprusside stimulates mitochondrial aconitase gene expression through the cyclic adenosine 3',5'-monosphosphate signal transduction pathway in human prostate carcinoma cells.

BACKGROUND: Mitochondrial aconitase (mACON), an iron-requiring enzyme, is a major target of nitric oxide (NO) in cells, which causes the oxidant-mediated disruption of the [4Fe-4S] prosthetic group of the enzyme. In this study, the effect of NO on mACON enzymatic activity and gene expression were investigated. METHODS: Three NO generators, sodium nitroprusside (SNP), S-nitoso-N-acetylpenicillamine (SNAP), and 3-morpholinosydnonimine (SIN) were used to determine the regulation of mACON enzymatic activity by NO. The effect of SNP on mACON, which modulates citrate secretion and cellular bioenergetics in PC-3 cells, was investigated by determining the effect of SNP on mACON gene expression using Western blot and transient gene expression assays. RESULTS: SNP upregulated mACON enzymatic activity and gene expression in PC-3 cells. However, treating cells with other NO generators, SNAP and SIN, resulted in decreased mACON enzymatic activity. The addition of ascorbic acid to the SNP treatment resulted in a decrease in mACON enzymatic activity and gene expression. Our results showed that both SNP and dibutyryl-cAMP increased the mACON promoter activity 2-fold while the effect was blocked by adding H-89. Mutation of the cAMP response element (CRE) to the AGAGCT abolished the activating effects of SNP and dibutyryl-cAMP on mACON promoter activity. CONCLUSIONS: These results establish the function of nitroprusside as a signaling molecule for mACON gene expression through the cAMP signal transduction pathway in human prostatic carcinoma cells.

Aconitate Hydratase↗
PubMed1998

Genotoxicity of nitric oxide produced from sodium nitroprusside.

Induction of mutation and micronucleus (MN) formation by nitric oxide (NO) was investigated in mammalian cells using sodium nitroprusside (SNP) as a drug donor of NO. Results showed that the concentration of NO2- in the tested solution rose according to time- and concentration-exposure to SNP. The treatment of SNP (0.5-8 micromol/ml with S9 or 2-8 micromol/ml without S9) induced a concentration-dependent increase in the mutation frequency at the gpt gene locus in g12 cells and caused a 13- (-S9) to 25- (+S9) fold increase above the background level at the highest concentration. A statistically significant increase in the number of micronucleated binucleated cells (MNBN) was also observed in treated groups. MNBN per thousand, MN per thousand and the proportion of the multiple micronuleated cells increased in a concentration-dependent manner in the concentration range of SNP (0.5-4 micromol/ml with S9 or 2-8 micromol/ml without S9). Our results indicate that SNP, an NO releasing drug, is genotoxic in g12 cells.

Cell Line↗
PubMed2007

A procedure for the detection of linkage with high density SNP arrays in a large pedigree with colorectal cancer.

BACKGROUND: The apparent dominant model of colorectal cancer (CRC) inheritance in several large families, without mutations in known CRC susceptibility genes, suggests the presence of so far unidentified genes with strong or moderate effect on the development of CRC. Linkage analysis could lead to identification of susceptibility genes in such families. In comparison to classical linkage analysis with multi-allelic markers, single nucleotide polymorphism (SNP) arrays have increased information content and can be processed with higher throughput. Therefore, SNP arrays can be excellent tools for linkage analysis. However, the vast number of SNPs on the SNP arrays, combined with large informative pedigrees (e.g. >35-40 bits), presents us with a computational complexity that is challenging for existing statistical packages or even exceeds their capacity. We therefore setup a procedure for linkage analysis in large pedigrees and validated the method by genotyping using SNP arrays of a colorectal cancer family with a known MLH1 germ line mutation. METHODS: Quality control of the genotype data was performed in Alohomora, Mega2 and SimWalk2, with removal of uninformative SNPs, Mendelian inconsistencies and Mendelian consistent errors, respectively. Linkage disequilibrium was measured by SNPLINK and Merlin. Parametric linkage analysis using two flanking markers was performed using MENDEL. For multipoint parametric linkage analysis and haplotype analysis, SimWalk2 was used. RESULTS: On chromosome 3, in the MLH1-region, a LOD score of 1.9 was found by parametric linkage analysis using two flanking markers. On chromosome 11 a small region with LOD 1.1 was also detected. Upon linkage disequilibrium removal, multipoint linkage analysis yielded a LOD score of 2.1 in the MLH1 region, whereas the LOD score dropped to negative values in the region on chromosome 11. Subsequent haplotype analysis in the MLH1 region perfectly matched the mutation status of the family members. CONCLUSION: We developed a workflow for linkage analysis in large families using high-density SNP arrays and validated this workflow in a family with colorectal cancer. Linkage disequilibrium has to be removed when using SNP arrays, because it can falsely inflate the LOD score. Haplotype analysis is adequate and can predict the carrier status of the family members.

Adaptor Proteins, Signal Transducing↗
PubMed2002

IL18 polymorphism is associated with an increased risk of Crohn's disease.

BACKGROUND: The etiology of inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, has not yet been made clear. However, inflammatory bowel disease is recognized as a multifactorial disease, and innate genetic factors might contribute to the pathogenesis. Cytokine genes are thought to be important in inflammatory bowel disease. Recently, interleukin 18, cloned as a novel proinflammatory cytokine, has been implicated in inflammatory bowel disease, especially Crohn's disease. METHODS: To identify germline mutations in patients with inflammatory bowel disease, the entire coding region of IL18 was examined using a DNA sequencing procedure. RESULTS: No functional mutations were found, but a novel single nucleotide polymorphism (SNP) was identified as TCA/TCC at codon 35. In patients with Crohn's disease, the frequency of TCC allele carriers was significantly higher than in healthy controls (chi2 = 9.35, P = 0.002229, OR = 2.58, 95% CI = 1.39-4.80). Also, the magnitude of the association was more remarkable in females (chi2 = 16.36, P = 0.000052, OR = 8.17, 95% CI = 2.73-24.41). The TCC allele at codon 35 of IL18 may increase the risk for Crohn's disease, especially in females. CONCLUSIONS: IL18 is probably one of several genes that determine susceptibility to Crohn's disease.

Adolescent↗
PubMed2004

Human genetics of plasma dopamine beta-hydroxylase activity: applications to research in psychiatry and neurology.

RATIONALE: Norepinephrine (NE) is a key neurotransmitter in the central and peripheral nervous systems. Dopamine beta-hydroxylase (DbetaH) catalyzes the synthesis of NE from dopamine (DA) and occurs in the plasma as a stable heritable trait. Studies of this trait have been useful in psychiatric and neurological research. OBJECTIVE: To selectively and critically review the literature on plasma DbetaH, and on recent progress understanding the molecular genetic basis for its inheritance. Based on this review, directions for future research in psychiatry and neurology will be suggested. METHODS: We selectively review the literature on the biochemical and molecular genetics of plasma DbetaH activity, as well as research on plasma and cerebrospinal fluid (CSF) DbetaH in psychiatric and neurological disorders. RESULTS: Strong evidence implicates DBH, the structural locus encoding DbetaH enzyme, as the major quantitative trait locus influencing plasma DbetaH activity, with one single nucleotide polymorphism (SNP) accounting for up to 50% of the variance. Mutations at DBH appear to be responsible for the rare syndrome of DbetaH deficiency. Some biochemical and genetic studies suggest associations between low plasma or CSF DbetaH and psychotic symptoms in several psychiatric disorders. Studies combining genotyping at DBH with biochemical measurement of plasma DbetaH have proven useful in studies of schizophrenia, cocaine-induced paranoia (CIP), depression, attention deficit hyperactivity disorder, and alcoholism. Such studies may also elucidate the contribution of noradrenergic dysfunction to a variety of symptoms in Parkinson's disease and other degenerative neurological disorders. CONCLUSIONS: A model is proposed, in which lower levels of DbetaH protein may lead to elevated ratios of DA to NE. This model may explain associations between lower plasma DbetaH activity and vulnerability to psychotic symptoms. Genotype-controlled analysis of plasma DbetaH holds promise for promoting further progress in research on psychiatric and neurological disorders.

Alcohol-Induced Disorders↗