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A Petronis

Publications and source records attributed to A Petronis.

52 records · Page 3Linked to original sources
PubMed1995

Association study between the dopamine D4 receptor gene and schizophrenia.

The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic clozapine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic origin matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48)n bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed.

Female↗
PubMed1995

DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls.

The DRD4 dopamine receptor is thus far unique among neurotransmitter receptors in having a highly polymorphic gene structure that has been reported to produce altered receptor functioning. These allelic variations are caused by a 48-bp segment in exon III of the coding region which may be repeated from 2-10 times. Varying the numbers of repeated segments changes the length, structure, and, possibly, the functional efficiency of the receptor, which makes this gene an intriguing candidate for variations in dopamine-related behaviors, such as alcoholism and drug abuse. Thus far, these DRD4 alleles have been investigated for association with schizophrenia, bipolar disorder, Parkinson's disease, and chronic alcoholism, and all have been largely negative for a direct association. We evaluated the DRD4 genotype in 226 Finish adult males, 113 of whom were alcoholics, many of the early onset type with features of impulsivity and antisocial traits. Genotype frequencies were compared to 113 Finnish controls who were free of alcohol abuse, substance abuse, and major mental illness. In 70 alcoholics and 20 controls, we measured CSF homovanillic acid (HVA), the major metabolite of dopamine, and 5-hydroxyindoleacetic acid (5-HIAA). No association was found between a particular DRD4 dopamine receptor allele and alcoholism. CSF concentrations of the monoamine metabolites showed no significant difference among the DRD4 genotypes. This study of the DRD4 dopamine receptor in alcoholics is the first to be conducted in a clinically and ethnically homogeneous population and to relate the DRD4 genotype to CSF monoamine concentrations. The results indicate that there is no association of the DRD4 receptor with alcoholism.

Adult↗
PubMed1995

Unstable genes--unstable mind?

OBJECTIVE: Over the past 3 years, reports of DNA alteration in myotonic dystrophy, fragile X syndrome (types A and E), Kennedy's disease, Huntington's disease, spinocerebellar ataxia type 1, and dentatorubral-pallidoluysian atrophy have identified a new class of human mutation, referred to as trinucleotide repeat amplification. All available evidence suggests that this unstable trinucleotide repeat DNA is the biological basis of the clinical phenomenon of genetic anticipation. Two components of anticipation, greater severity and earlier age at onset in subsequent generations, have been widely observed in schizophrenia and bipolar affective disorder. Thus, a reanalysis of the genetics of major psychosis from the perspective of unstable DNA is of significant interest. METHOD: The authors reviewed the available literature on anticipation and related phenomena in major psychosis and reevaluated the family, twin, and adoption study data. RESULTS: The unstable DNA concept competes well with the traditional multifactorial polygenic theory; many deviations from a single gene mode of inheritance in psychiatric twin and family studies, which previously served as strong proof for more than one etiologic gene, can be easily explained by the non-Mendelian behavior of unstable DNA. In addition, this new paradigm provides a simple explanation for unclear issues in the genetics of major psychosis, such as the identical rate of psychosis in the offspring of discordant monozygotic twins. CONCLUSIONS: The major advantage of the unstable DNA hypothesis over the multifactorial polygenic theory lies in the possibility of falsifying the unstable DNA hypothesis by two independent laboratory strategies: a classical linkage analysis and a set of novel methods for the direct detection of unstable DNA sites.

Adult↗
PubMed1995

Genetic anticipation in schizophrenia: pro and con.

Recently, it has been demonstrated that unstable trinucleotide repeats are the etiologic factor in myotonic dystrophy, fragile-X syndrome, Kennedy's disease, Huntington's disease, spinocerebellar ataxia type 1, and dentatorubral-pallidoluysian atrophy. All available evidence suggests that these expanded trinucleotide repeats, or unstable DNA, are the biological basis of the clinical phenomenon of genetic anticipation. Two components of anticipation, increased severity and earlier age of onset in subsequent generations, have been widely observed in schizophrenia. We review the evidence for and against genetic anticipation in schizophrenia. Although the major criticisms of the anticipation hypothesis can be questioned, so can the evidence in favor of it. We conclude that molecular genetic approaches might be the most useful means of resolving ambiguity in clinical arguments about the origin of the anticipation-like phenomenon in schizophrenia.

Age of Onset↗
PubMed1994

Analysis of the D4 dopamine receptor gene variant in an Italian schizophrenia kindred.

BACKGROUND: Among the different dopamine receptors, the D4 dopamine receptor is of particular interest in schizophrenia because of its high affinity for the atypical neuroleptic clozapine. Recently, the gene for the D4 dopamine receptor has been cloned and a new and intriguing polymorphism has been described. Different versions of the receptor have varying affinity for clozapine, and thus variant froms of D4 with differing pharmacologic activity exist in the human population. Our hypothesis was that these variants play a role in susceptibility to psychotic illness. Thus, our objective was to test the D4 dopamine receptor genes for linkage to schizophrenia. METHODS: Our genetic linkage study was carried out in a large Italian kindred segregating schizophrenia. Diagnoses were made by using a structured clinical interview and a consensus diagnosis was established. For the computer analysis, 80 members of the family were constructed into a linked set of relatives with 15 of these individuals affected by schizophrenia. The functional variants of the D4 dopamine receptor gene were identified by a combination of Southern blot techniques and the polymerase chain reaction. The gene for tyrosine hydroxylase (TH) was also tested for linkage to schizophrenia in this family. Linkage analyses were done with both a single-locus and a two-locus model. RESULTS: Our results revealed significantly negative lod scores in the region of the D4 dopamine receptor gene and the TH gene. The application of different models of transmission for schizophrenia had an effect on the magnitude of the lod scores, but did not modify the direction of the results. CONCLUSIONS: Our results provide significant evidence for exclusion for linkage between schizophrenia and the dopamine D4 receptor gene and the TH gene under the models specified. Furthermore, we tabulated the distribution of D4 dopamine gene variants in the diseased vs healthy individuals in the family and the results showed that no specific form of the receptor gene is significantly associated with the presence of schizophrenia in the family. Our study does not exclude the possibility that regulatory elements of the D4 dopamine gene located elsewhere in the genome may be involved in the etiology of schizophrenia.

Blotting, Southern↗
PubMed1994

Genetic linkage evaluation of twenty-four loci in an eastern Canadian family segregating Darier's disease (keratosis follicularis).

BACKGROUND: Darier's disease (keratosis follicularis) is known to have a genetic cause as evidenced by its autosomal dominant transmission in families. The gene causing this disease has not been discovered. OBJECTIVE: During an ongoing linkage study of schizophrenia, a family segregating Darier's disease was found. This family is being studied in an attempt to locate prospective regions that may contain the Darier's disease gene. METHODS: Two genetic strategies are being employed: (1) testing candidate genes for the disorder and (2) scanning the entire genome with polymerase chain reaction-based microsatellite markers. RESULTS: Thirty-nine marker systems located on chromosomes 1, 2, 4, 5, 6, 9, 11, 12, 16, 17, 22, X, and Y have been genotyped. Slightly positive lod scores were achieved between six markers and Darier's disease. The remaining 33 markers were nonsegregating or indeterminate, or revealed an obligate recombinant. CONCLUSION: Linkage analysis can lead to localization of the gene causing Darier's disease. In these preliminary studies low positive lod scores were obtained, potentially pointing to the chromosomal location of the Darier's disease gene.

Chromosome Mapping↗
PubMed1994

Dopamine D4 receptor repeat: analysis of different native and mutant forms of the human and rat genes.

Recent molecular characterization of the human D4 gene has revealed the existence of various polymorphic forms of this receptor. These variations are found in the putative third cytoplasmic loop region and encode a variable number of repeats of 16 amino acids in length. In the present study we have compared the pharmacological binding profiles of seven different polymorphic variants of the human D4 receptor, the rat D4 receptor, and two different human D4 receptor mutants that were deleted in the repeat sequence. For this purpose we cloned the rat D4 receptor gene and compared its gene structure and its pharmacological binding profile with those of the D4.4 and D4.7 genes. The rat and human D4 genes display a high degree of sequence similarity, especially in the coding regions. An Alu repeat sequence was identified in the first intron of the human D4 gene but is not present in the rat D4 gene. Furthermore, using the polymerase chain reaction we cloned 3-, 5-, 6-, and 9-fold repeat sequences. These cloned repeat sequences were used for the reconstruction of full length cDNAs encoding D4.3, D4.5, D4.6, and D4.9, respectively. These novel forms of the human D4 receptor, as well as the previously cloned D4.2, D4.4, and D4.7 forms, were transiently expressed in COS-7 cells. All of the different forms of the human and rat D4 receptors and repeat deletion mutants displayed similar binding profiles for all ligands tested, although small differences were observed. The affinity for dopamine could be decreased by guanosine-5'-(beta, gamma-imido)triphosphate with the different forms of the D4 receptor, including the two receptor mutants that were deleted in the repeat sequence. These data suggest that the polymorphic repeat sequence has little influence on D4 binding profiles and might not be essential for G protein interaction.

Amino Acid Sequence↗
PubMed1993

A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11.

We report the cloning of a gene, intronless in its coding region, which we have named APJ. This gene was cloned using the polymerase chain reaction (PCR), with a set of primers designed on the basis of the conservation that members of G protein-coupled receptors (GPCR) have in their transmembrane (TM) regions. The putative receptor protein, APJ, shares closest identity to the angiotensin receptor (AT1) ranging from 40 to 50% in the hydrophobic TM regions of these receptors. The transcripts for this gene were detected in many regions of the brain. PCR analysis of somatic cell lines found APJ-related sequences to be only present on chromosome 11, and high-resolution mapping by fluorescence in situ hybridization (FISH) sublocalized APJ on band q12.

Amino Acid Sequence↗
PubMed1993

An Alu sequence interrupts a human 5-hydroxytryptamine1D receptor pseudogene.

Molecular cloning studies have now identified six HTR genes encoding the biosynthesis of the structurally homologous human serotonin (5-hydroxytryptamine; 5-HT) receptors, namely 5-HTR1A, 5-HTR1B, 5-HTR1C, 5-HTR1D, 5-HTR2 and 5-HTRS31. Several of these receptors are encoded by intronless genes, and we now report the cloning of another intronless serotonergic HTR gene. This gene was cloned by a method using the polymerase chain reaction. The nucleotide sequence of this gene is most closely homologous to the 5-HTR1D gene; however, several stop codons, frame shifts and deletions are present in the coding region suggesting that this is a pseudogene which could not encode a functional receptor. Sequence analysis also revealed that the coding sequence of this pseudogene is disrupted by insertion of a 283-bp Alu repeat sequence.

Amino Acid Sequence↗
PubMedDate not supplied

A SmaI PCR-RFLP in the 5' noncoding region of the human D4 dopamine receptor gene (DRD4).

The D4 dopamine receptor is of great interest for research into neuropsychiatric disorders and psychopharmacology in light of the fact that it binds the antipsychotic medication clozapine with higher affinity than does any other dopamine receptor [Van Tol, et al., Nature 1991; 350:610-614]. Furthermore, in the third exon of this gene, there is an unusual 48-bp repeat sequence polymorphism that produces variable receptor protein sequences that have different affinities for the drug clozapine [Van Tol, et al., Nature 1992; 358:149-152]. A new two-allele PCR-based SmaI restriction fragment length polymorphism (RFLP) was revealed at the human DRD4 locus employing a new method for the detection of PCR-able RFLPs. The polymorphic SmaI restriction site is located in the 5' noncoding region of the human DRD4 gene. This SmaI PCR-RFLP serves as an additional marker for genetic linkage and association studies between DRD4 and neuropsychiatric disorders.

Base Sequence↗
PubMedDate not supplied

An association study between schizophrenia and the dopamine receptor genes DRD3 and DRD4 using haplotype relative risk.

Our work investigates the relationship between genetic factors and schizophrenia, seeking to identify a gene or genes associated with the clinical form of the disease in a group of Italian patients. In pursuit of the 'dopaminergic hypothesis' of schizophrenia, we explored a possible etiologic role of two dopamine receptor genes, DRD3 and DRD4, that have been repeatedly suggested as factors in the pathophysiology of the disease. We typed DNA polymorphisms in each of the genes that code for variation in the amino acid sequence of the receptor protein. An innovative design using parental chromosomes as controls--the 'haplotype relative risk' strategy--represents a significant improvement over previous association studies in psychiatric genetics. Our results suggest that, at least in our well-defined population, the candidate genes DRD3 and DRD4 do not appear to play a major role in the genetic etiology of schizophrenia.

Adult↗
PubMedDate not supplied

[Dopaminergic system genes in Mexican schizophrenics].

This investigation reports an association study with alleles of the dopaminergic system genes (tyrosine hydroxylase (TH), D2 and D4 receptors) in schizophrenic patients and non-schizophrenic subjects. The genotypes were typed using a polymerase chain reactions PCR-based CA repeat polymorphisms. There were no significant associations between the studied alleles and schizophrenia. Also, a linkage analysis was performed using the same genes (TH, D2 and D4) in two multiple affected schizophrenic families. There was no linkage among any of three genes and schizophrenia. The maximum lod score (Z = 0.43, theta = 0.10 penetrance 100%) was for the tyrosine hydroxylase gene. Linkage analysis significantly excluded the D2 receptor gene (Z = 5.6, theta = 0.01), assuming an autosomal dominant pattern and complete penetrance, However, when the lod scores were calculated with other penetrance values, they lost significance.

Adult↗