Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-four-hour excretion (expressed per gram of creatinine) of the norepinephrine metabolites 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and normetanephrine (NME) was measured in children with attention deficit hyperactivity disorder (ADHD) and in normal subjects matched for age and education. In contrast to findings with Tourette syndrome patients, in the ADHD patients there was no significant difference in excretion of MHPG and NME from control values.
Mol Chem Neuropathol
PMID:Urinary excretion of MHPG and normetanephrine in attention deficit hyperactivity disorder. 846 90

We identified unusual mutations in the T3 receptor (TR) beta gene in a 6-year-old Japanese girl with generalized resistance to thyroid hormone. Two consecutive base substitutions, T to A and C to A at nucleotide positions 1637 and 1638, respectively, changed the 451st codon coding for Phe(TTC) to stop codon (TAA), resulting in an 11-amino acid carboxyl(C)-terminus truncation. The patient was a heterozygote. Western blotting using an anti-TR antibody demonstrated the truncated receptor protein. The patient showed severe mental retardation (IQ41), disturbance in speech development, and attention deficit hyperactivity disorder. Thyroid functional status by clinical evaluation was considered within the normal range in spite of high serum thyroid hormone levels (T4 725.9 nmol/l, T3 12.7 nmol/l, FT4 166.0 pmol/l). TSH increased from 0.6 to 24 mU/L after TRH (150 micrograms) injection. TSH secretion as well as 123I-uptake was suppressed only partially by T3 (75 micrograms/day for a week). Close examination of thyroid functions and TR beta gene analysis were not possible in the family, except for paternal grandmother and one of her two sisters who showed no abnormality. The patient's truncated TR beta showed very low T3 binding activity (Ka = 0.1 x 10-10 M), transcriptional activity, and a very strong dominant negative effect. When co-expressed with wild-type TR beta at the molar ratio 1:1 in CV-1 cells, the mutant receptor inhibited the wild-type TR beta transcriptional activity by 74% at 10 nM T3. Even 1 microM T3 could not normalize these impaired functions.
Mol Cell Endocrinol 1995 Oct 30
PMID:Two consecutive nucleotide substitutions resulting in the T3 receptor beta gene resulting in an 11-amino acid truncation in a patient with generalized resistance to thyroid hormone. 867 55

Dopamine is believed to play a major role in the manifestation of attention deficit hyperactivity disorder (ADHD), which affects 3-6% of school-age children and shows evidence of familiarity. The dopamine D4 receptor, which is preferentially distributed in cortical and limbic regions of the brain, is currently of major interest because of the high degree of functionally relevant variability in its gene (DRD4), and the association of this gene with Novelty Seeking behavior. We examined the variability in the length of a region of DRD4 that contains a 48-bp repeat sequence in children with ADHD and controls matched for ethnicity. ADHD children differed from controls in that the 7-fold repeat form of DRD4 occurred significantly more frequently than in the control sample. This form of the receptor has previously been shown to mediate a blunted intracellular response to dopamine. Although ADHD is likely to be multifactorial in its etiology and its heritability is likely to be polygenetic, the present findings suggest that polymorphic variation in the gene encoding the D4 dopamine receptor may be a contributing factor in the expression of symptoms associated with ADHD.
Mol Psychiatry 1996 May
PMID:Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. 911 26

Attention deficit hyperactivity disorder (ADHD) is a common condition of childhood the symptoms of which include inattention, excessive motor activity, inpulsivity and distractibility. It is strongly familial and twin and adoption studies suggest that the familiality is due, at least in part, to shared genes. Gillis et al found concordance rates in ADHD for MZ and DZ twins of 81% and 29% respectively. Stimulant drugs (eg, methylphenidate) are effective in the treatment of ADHD and inhibit the dopamine transporter. This has led to the development of a hypodopaminergic hypothesis for the disease. Cook et al examined a 3' variable number of tandem repeat (VNTR) polymorphism at the dopamine transporter gene (DAT1) in a sample of 49 ADHD patients and their parents, using the haplotype relative risk (HRR) method. They found a significant association (chi 2 = 7.29, 1 d.f., P = 0.007) between ADHD and the 480-bp DAT1 VNTR allele. The authors stressed the importance of independent replication and we have achieved this in a study of 40 probands and their parents, using the same robust HRR method. As in the study of Cook et al we found that the 480-bp allele was preferentially transmitted to ADHD probands (chi 2 = 6.07, 1 d.f., P = 0.014).
Mol Psychiatry 1997 Jul
PMID:Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. 924 71

Previously in this journal, we reported an association of the dopamine D4 receptor gene (DRD4) and attention deficit hyperactivity disorder (ADHD). In a population-association (case-control) study of 39 children with a refined phenotype of ADHD and 39 ethnically matched controls, we observed an increased percentage of the 7 repeat allele (29% vs 12%) and the 7+ genotype (49% vs 21%) in the ADHD group compared to the control group. In a replication and an extension of our initial study, we recruited another sample of ADHD subjects and found percentages of the 7 repeat allele (28%) and the 7+ genotype (48%) consistent with our previous findings. We used a family-based approach to evaluate a predicted association of DRD4 and ADHD based on a test of allele transmission focused on the 7 repeat allele. We identified 52 families based on the diagnosis of the refined phenotype of ADHD in the proband and the availability of DNA from both biological parents as well as the proband. Haplotype relative risk (HRR) analysis was performed to test our a priori hypothesis and produced significant results (chi-square = 4.65, P < 0.035). This provides additional evidence that the DRD4 gene is associated with a refined phenotype of ADHD.
Mol Psychiatry 1998 Jan
PMID:Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach. 949 11

How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.
Mol Psychiatry 1998 Sep
PMID:Anti-hyperactivity medication: methylphenidate and amphetamine. 977 67

A polymorphism in the dopamine receptor 4 gene (DRD4) has been related to novelty seeking, Tourette's syndrome, and attention deficit hyperactivity disorder (ADHD). The variability is in a 48-bp repeat in exon 3 of the gene (a transmembrane region). This study examined the relation of the 7-repeat (i.e., high-risk) allele to questionnaire-based diagnoses of ADHD (both combined type and inattentive type). Several positive findings were obtained for ADHD-inattentive type. In an association test, the 7-repeat allele occurred more frequently in children with ADHD-inattentive type than in control children. In genetically discordant sibling pairs, the sibling with a greater number of 7-repeat alleles displayed more inattentive symptoms than his/her co-sibling with fewer 7-repeat alleles. For ADHD-combined type, the 7-repeat allele frequency was greater than that in the control sample. However, a quantitative transmission disequilibrium test yielded no significant linkage of the 7-repeat allele with hyperactive-impulsive symptoms. A categorical TDT yielded no significant findings, but the number of transmissions was small, especially for ADHD-inattentive type.
Mol Psychiatry 1998 Sep
PMID:Dopamine DRD4 receptor polymorphism and attention deficit hyperactivity disorder. 1061 Feb 19

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral problem afflicting 5-10% of children and adolescents and persisting into adulthood in 30-50% or more of cases. Family, twin, and adoption studies suggest genetic factors contribute to ADHD and symptoms of inattention, impulsivity, and hyperactivity. Because stimulant intervention is effective in reducing ADHD symptoms in about 70-80% of cases, molecular genetic investigations of genes involved in dopamine regulation are currently underway by many groups. In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hoste and colleagues found an increase of a 7-repeat variant of a 48-bp VNTR in exon 3 among ADHD subjects compared to controls. Swanson and colleagues replicated this finding in a sample of 52 ADHD probands and their biological parents using a haplotype relative risk analysis. Here, we describe linkage investigations of the VNTR and ADHD in affected sibling pair (ASP) families and singleton families using both the transmission disequilibrium test (TDT) and a mean test of identity-by-descent (IBD) sharing. Using the TDT in the total sample, the 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing among ASPs. In the current sample, the 7 allele attributes a 1.5-fold risk for developing ADHD over non-carriers of the allele estimated under a model described by Risch and Merikangas.
Mol Psychiatry 1998 Sep
PMID:Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder. 977 67

Attention deficit hyperactivity disorder (ADHD) is a common disorder of childhood characterized by inattention, excessive motor activity, impulsivity, and distractibility. It is associated with serious disability in children, adolescents and adults. The etiology of the disorder is unknown, but it has a strong genetic component. Pharmacological and biochemical studies have suggested that dopaminergic and noradrenergic systems are involved. Using a sample of affected children and their parents we have found preferential transmission of alleles at polymorphisms at the dopamine transporter (DAT1), RR=1.2 (1.05-1.37), P=0.006, re-confirming and extending our previous findings for DAT1 (new sample one-tailed P=0.039); dopamine-beta-hydroxylase (DBH), RR=1.31 (1.09-1.56), P=0.0027; and the dopamine D5 receptor (DRD5), RR=1.67 (1.29-2.15), P=0.00005. Transmission of the 'associated' alleles at DAT1 and DBH is stronger in familial cases, RR(DAT1)=1.29 (1.04-1.59), RR(DBH)=1.49 (1.10-2.00), but for DRD5, transmission is stronger in non-familial cases, RR=1.59 (1.05-2.42). TDT analysis of complete trios supports the HHRR analysis, with P<0.05, for DAT1 P<0.005 and DBH and P<0.01 for DRD5. Attributable fractions for DAT1, DBH and DRD5 are calculated at 0.08, 0.12 and 0.20 respectively.
Mol Psychiatry 1999 Mar
PMID:Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. 1020 53

Extraordinary progress has been made in the molecular, genetic, anatomical, and pharmacological characterization of dopamine D4 receptors in animal and human brain. Clarification of the neurochemical and physiological roles of these cerebral receptors is emerging. Postmortem neuropathological studies have inconsistently linked D4 receptors to psychotic disorders, and genetic studies have failed to sustain conclusive associations between D4 receptors and schizophrenia. However, associations are emerging between D4 receptors and other neuropsychiatric disorders, including attention deficit hyperactivity disorder, mood disorders, and Parkinson's disease, as well as specific personality traits such as novelty-seeking. Selective D4 agonists and antagonists have been developed as useful experimental probes. D4antagonists, so far, have proved ineffective in treatment of schizophrenia, but testing in a broader range of disorders may yield clinically useful drugs. D4 receptors appear to have broad implications for the pathophysiology of neuropsychiatric illnesses and their improved treatment.
Mol Psychiatry 1999 Nov
PMID:Dopamine D4 receptors: significance for molecular psychiatry at the millennium. 1057 34


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