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P Propping

Publications and source records attributed to P Propping.

At least 73 records · Page 4Linked to original sources
PubMed2000

Association analysis between a regulatory-promoter polymorphism of the human monoamine oxidase A gene and idiopathic generalized epilepsy.

Monoaminergic neurotransmission plays an important role in the regulation of neuronal network excitability and seizure activity. Therapeutic inhibition of the mitochondrial enzyme monoamine oxidase A (MAO-A), which is involved in the degradation and inactivation of monoaminergic neurotransmitters, has been shown to confer a potent anticonvulsant effect. These and other findings suggest a possible role of the X-linked MAO-A gene in epileptogenesis. Therefore, our study was designed to test for an association between a novel MAO-A gene promoter polymorphism and common subtypes of idiopathic generalized epilepsy (IGE). The length of a 30-bp repetitive sequence approximately 1.2 kb upstream of the ATG initiation codon was assessed in 126 patients with juvenile myoclonic epilepsy (JME), 122 patients with idiopathic absence epilepsy (IAE), and 248 healthy controls of German descent. Both sexes were analyzed separately. Although we observed a trend towards a lower number of heterozygotes carrying the 3 and 4 copy alleles in female IAE patients (chi2 = 3.813, df = 1, P = 0.053), allele frequencies did not deviate significantly between patients and controls. Thus, our results do not provide evidence for a contribution of the functional MAO-A gene promoter polymorphism to the pathogenesis of common IGE subtypes.

Adult↗
PubMed2000

Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.

Inherited limb malformations provide a valuable resource for the identification of genes involved in limb development. Brachydactyly type B (BDB), an autosomal dominant disorder, is the most severe of the brachydactylies and characterized by terminal deficiency of the fingers and toes. In the typical form of BDB, the thumbs and big toes are spared, sometimes with broadening or partial duplication. The BDB1 locus was previously mapped to chromosome 9q22 within an interval of 7.5 cM (refs 9,10). Here we describe mutations in ROR2, which encodes the orphan receptor tyrosine kinase ROR2 (ref. 11), in three unrelated families with BDB1. We identified distinct heterozygous mutations (2 nonsense, 1 frameshift) within a 7-amino-acid segment of the 943-amino-acid protein, all of which predict truncation of the intracellular portion of the protein immediately after the tyrosine kinase domain. The localized nature of these mutations suggests that they confer a specific gain of function. We obtained further evidence for this by demonstrating that two patients heterozygous for 9q22 deletions including ROR2 do not exhibit BDB. Expression of the mouse mouse orthologue, Ror2, early in limb development indicates that BDB arises as a primary defect of skeletal patterning.

Amino Acid Sequence↗
PubMed2000

DRD4 exon III VNTR polymorphism-susceptibility factor for heroin dependence? Results of a case-control and a family-based association approach.

Dopaminergic abnormalities are implicated in the pathogenesis of substance abuse.1 Recently, two reports have been published suggesting an association between opioid dependence and presence of long alleles of the dopamine D4 receptor (DRD4) gene exon III VNTR.2, 3 We have attempted to replicate this finding using a two-tiered strategy employing independent case-control and family-based association samples. Our study was possibly the largest candidate gene association study to date on opioid dependence in a sample of 815 subjects, 396 of whom were patients. We found long alleles of the DRD4 exon III VNTR in similar frequency among 285 heroin addicts and 197 controls. Furthermore, no preferential transmission of long alleles to affected offspring was observed in a sample of 111 patients and their parents. Our results, therefore, do not support the hypothesis that alleles of the DRD4 exon III VNTR are susceptibility factors for opioid dependence in man. Molecular Psychiatry(2000) 5, 101-104.

Adult↗
PubMed2000

Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1).

The dopamine transporter (DAT) plays a central role in dopaminergic neurotransmission in the human brain. Genetic association studies have used a variable number of tandem repeat (VNTR) polymorphism in the 3'-flanking region of the dopamine transporter gene (DAT1) to implicate the DAT in the development of various neuropsychiatric disorders. In this study, we have examined the possibility that a mutation exists in the coding region of the DAT1 gene which through linkage disequilibrium accounts for the observed associations. The complete coding region, as well as exon-intron boundaries, was screened in 91 unrelated individuals including 45 patients with bipolar affective disorder and 46 healthy control individuals by the means of single strand conformation analysis. Our findings suggest that the DAT1 gene is highly conserved since we detected only two rare missense substitutions (Ala559Val, Glu602Gly) and three silent mutations (242C/T, 1342A/G, and 1859C/T) in the whole coding region. Five sequence variants were observed in intronic sequences but none affects known splice sites. The lack of frequent variants of possible functional relevance indicates that genetic variation in the coding region of the DAT1 gene is not responsible for the previously observed associations with neuropsychiatric disorders. The two rare missense substitutions were found in single bipolar patients but not in controls. Investigation of the patients' families revealed independent segregation between the Ala559Val variant and affective disorder. The Glu602Gly variant was inherited by the proband from an affected father. It therefore remains possible that Glu602Gly may be a rare cause of bipolar affective disorder.

Amino Acid Substitution↗
PubMed2000

A distinct gene close to the hairless locus on chromosome 8p underlies hereditary Marie Unna type hypotrichosis in a German family.

BACKGROUND: Hypotrichosis of the Marie Unna type (HMU) is a rare autosomal dominant disorder characterized by male-pattern hair loss with childhood onset and anomalies of the hair shaft. OBJECTIVES: We aimed to evaluate a number of chromosomal loci as possible candidate regions for HMU. METHODS: A linkage analysis was performed in a large German family using microsatellite markers spanning candidate regions on chromosomes 8, 12 and 17. RESULTS: We found that the HMU locus maps to chromosomal region 8p21 in a 13.01-cM interval between markers D8S1145 and D8S1771. This interval harbours the hairless gene (HR). Mutational analysis of HR on the genomic and transcript levels revealed no pathogenic mutation. CONCLUSIONS: Our findings, together with a recent report of two unrelated families of Dutch and British origin, provide evidence for a hair growth regulatory gene distinct from HR in chromosomal region 8p21.

Adult↗
PubMed2000

Pharmacological properties of naturally occurring variants of the human norepinephrine transporter.

The human norepinephrine transporter (hNET) gene has five sequence polymorphisms that predict amino acid substitutions in the transporter protein: Val69Ile, Thr99Ile, Val245Ile, Val449Ile, and Gly478Ser. In order to functionally characterize the naturally occurring transporter variants, we used site-directed mutagenesis to establish the hNET variants and compared some basic pharmacological properties (uptake of norepinephrine and its inhibition by the tricyclic antidepressant desipramine) in COS-7 cells transiently expressing variant hNETs and wild-type hNET. None of the hNET variants displayed changes in the potency (Ki) of desipramine for inhibition of norepinephrine uptake. Furthermore, variants Val69Ile, Thr99Ile, ValZ45Ile, and Val449Ile did not affect kinetic constants (Km, Vmax) of norepinephrine uptake. However, COS-7 cells expressing the hNET variant Gly478Ser displayed an approximately four-fold increase in the Km for norepinephrine, while the Vmax was unaffected. The increase in the Km, which is equivalent to a four-fold reduction in the affinity of the variant hNET for its natural substrate norepinephrine, indicates that the glycine in position 478 is part of a substrate recognition domain. The reduced clearance of released norepinephrine by reuptake through the Gly478Ser variant might cause an increase in the synaptic and the circulating concentration of norepinephrine. Elevated norepinephrine concentrations have been associated with human diseases and it will be interesting to explore a possible contribution by the Gly478Ser variant to certain disease states.

Amino Acid Substitution↗
PubMed2000

Exonic variants of the GABA(B) receptor gene and panic disorder.

The enhancement of GABAergic neurotransmission has been closely linked to antipanic drug efficacy. This is the first study to investigate a putative association of exonic sequence variants of the human GABA(B) receptor 1 (GABA(B)R1) gene and susceptibility to panic disorder. Three DNA sequence variants in exons 1a1, 7 and 11 were assessed by polymerase chain reaction-based restriction fragment length polymorphism in a case-control study among patients with panic disorder with and without agoraphobia (DSM III-R criteria) and blood donors. There was no indication of an increased vulnerability to panic disorder or agoraphobia with respect to the allelic variants under study.

Agoraphobia↗
PubMed2000

Polymorphic MAO-A and 5-HT-transporter genes: analysis of interactions in panic disorder.

Recurrent panic attacks, anticipatory anxiety and phobic avoidance characterise panic disorder. The influence of genetic factors on liability to the disease has been the object of several linkage and association studies and appears to relate to an oligo- or polygenic rather than a monogenic mode of inheritance. Recently, an excess of high activity monoamine oxidase A (MAO-A) gene promoter alleles was found in female patients with panic disorder. An analysis of possible synergistic effects of the MAO-A gene promoter variant and the short serotonin transporter (5-HTT) gene promoter variant in panic disorder was performed in a German and an Italian sample (combined panic disorder n = 144, combined controls n = 175). There was no significant difference in odds ratios, suggesting that the observed increase of genetic liability by the long MAO-A gene promoter allele is not modified by the 5-HTT gene promoter polymorphism.

Adult↗
PubMed1999

Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia.

Genetic factors and dopamine receptor dysfunction have been implicated in the pathophysiology of schizophrenia. Recently, an association between a putative functional promoter polymorphism (-141C Ins/Del) in the dopamine D2 receptor gene and schizophrenia was reported. We investigated unrelated Swedish schizophrenic patients (n = 129) and control subjects (n = 179) for the same polymorphism. Similarly to a previous Japanese report, the - 141C Del allele frequency was significantly lower in patients than controls (chi2=4.4, 1 df, p<0.05; odds ratio 0.49, 95% confidence interval 0.26-0.91). The present and previous results may indicate that the -141C Ins/Del dopamine D2 receptor gene polymorphism affects susceptibility to schizophrenia.

Adult↗
PubMed1999

Human delta-opioid receptor gene and susceptibility to heroin and alcohol dependence.

In the present study, we tested the hypothesis that addictive behavior may be influenced by genetic variation in the human delta-opioid receptor gene. We investigated the contribution of a silent T to C change in the coding region to the development of heroin and alcohol dependence using large case-control and family-based association samples. Presence of the C allele was previously reported to significantly increase the risk for heroin dependence. In the present study, however, we did not find statistically significant differences between patients and controls nor did we find preferential transmission of the C allele from parents to affected offspring. Our results, therefore, do not support an association between genetic variation of the delta-opioid receptor and addictive behavior in man.

Adult↗
PubMed1999

No association between serotonin transporter gene polymorphisms and personality traits.

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study.

Adult↗
PubMed1999

Tourette syndrome and the norepinephrine transporter gene: results of a systematic mutation screening.

Tourette syndrome (TS) is a complex inherited neuropsychiatric disorder characterized by multiple motor and phonic tics. Involvement of central norepinephrine mechanisms is suggested by central norepinephrinic hyperactivity in patients with TS and by the therapeutic effects of the presynaptic alpha2-adrenergic agonist clonidine. The norepinephrine transporter gene (NET) was systematically screened by single-strand conformation analysis for genetic variants, including the whole coding region and adjacent exon-intron boundaries in 43 patients with TS and 46 healthy controls. We detected 12 DNA sequence variants, among them four missense mutations (Val69Ile, Thr99Ile, Va1245Ile, and Gly478Ser). The observed missense mutations may alter conformational rearrangements during gating of the transporter, assembly of subunits, and norepinephrine-specific uptake affinity. Allele frequency and genotype distribution of the genetic variants showed no differences between TS patients and controls. No mutation of likely functional significance was found that distinguished TS patients from healthy controls, indicating that genetic variants of the NET gene are not causally related to Tourette syndrome.

Adolescent↗
PubMed1999

Peutz-Jeghers syndrome: four novel inactivating germline mutations in the STK11 gene. Mutations in brief no. 227. Online.

The diagnosis of Peutz-Jeghers syndrome is based on the occurrence of hamartomatous gastrointestinal polyps and perioral pigment spots. In view of the development of hamartomatous polyps in several syndromes and the variability of pigment spots in Peutz-Jeghers patients, identification of affected individuals is difficult. Recently, germline mutations in the STK11 gene have been reported as a molecular cause of Peutz-Jeghers syndrome. We present four novel inactivating mutations identified by direct sequencing of all 9 exons of the STK11 gene in 4 patients suggestive of Peutz-Jeghers syndrome: three frameshift mutations (125-137del; 474-480del; 516-517insT) and one nonsense mutation (Q220X). Our data obtained in these patients and in those reported previously emphasize the diagnostic value of histological discrimination between different types of hamartomatous polyps and of molecular analysis, particularly in cases with no family history of the disease.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

Genetic linkage analysis with dyslexia: evidence for linkage of spelling disability to chromosome 15.

Dyslexia (reading and spelling disability) is one of the most frequently diagnosed disorders in childhood. Twin studies of dyslexia have indicated that deficits in spelling are substantially heritable and that the heritability of spelling deficits is higher than the heritability of reading deficits. We conducted a linkage study for spelling disability in seven multiplex families from Germany. Following previously reported linkage findings of components of dyslexia to chromosome 6p21-p22 and 15q21, we genotyped 26 microsatellite markers covering all of chromosome 6, and 13 microsatellite markers covering all of chromosome 15. While the chromosome 6 data were negative, results from chromosome 15 markers supported a locus on 15q21. The highest two-point LOD score was 1.26 with marker D15S143 at theta = 0. A multipoint LOD score of 1.78 (p = 0.0042) was achieved with a maximum at D15S132. Thus, our results provide independent support for a dyslexia gene on the long arm of chromosome 15.

Child↗
PubMed1999

Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families.

Previously reported linkage of bipolar affective disorder to DNA markers on chromosome 18 was reexamined in a large sample of German bipolar families. Twenty-three short tandem repeat markers were investigated in 57 families containing 103 individuals with bipolar I disorder (BPI), 26 with bipolar II disorder (BPII), nine with schizoaffective disorder of the bipolar type (SA/BP), and 38 individuals with recurrent unipolar depression (UPR). Evidence for linkage was tested with parametric and non-parametric methods under two definitions of the affected phenotype. Analysis of all 57 families revealed no robust evidence for linkage. Following previous reports we performed separate analyses after subdividing the families with respect to the sex of the transmitting parent. Fourteen families were classified as paternal and 12 families as maternal. In 31 families the parental lineage of transmission of the disease could not be determined ('either' families). Evidence for linkage was obtained for chromosomal region 18p11.2 in the paternal families and for 18q22-23 in the 'either' families. The findings on 18p11.2 and 18q22-23 support prior evidence for susceptibility loci in these regions. The parent-of-origin effect on 18p11.2 is confirmed in our sample. The delineation of characteristics of 'either' families requires further study.

Bipolar Disorder↗