A Serotonin Receptor Gene (5HT1A) Variant Found in a Tourette's Syndrome Patient

doi:10.1006/bbrc.1996.0322

Biochemical and Biophysical Research Communications

Volume 219, Issue 3, 27 February 1996, Pages 853-858

https://doi.org/10.1006/bbrc.1996.0322 Get rights and content

Abstract

Serotonergic pathway disturbances have been implicated in neuropsychiatric disorders such as Tourette's syndrome (TS), substance abuse, and depression. In order to search for the presence of an association between these neuropsychiatric disorders and particular serotonin receptors isolated from these patients, we have started to analyze the structure of these receptor genes. We now report that a missense nucleotide change in the 5HT1A receptor gene produces a variant form of the 5HT1A receptor (Arg₂₁₉to Leu) identified in DNA extracted from a TS patient. Also, in several DNA samples examined, both in controls and in the patients, we found a second missense nucleotide change which resulted in an amino acid change (Asn₄₁₇to Lys) located in the carboxyl tail of the receptor. Several other polymorphic changes have been reported previously in the human 5HT1A receptor and we have also confirmed these findings in our samples.

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Cited by (45)

Molecular biology of 5-HT receptors
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Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine neurotransmitter whose effects are mediated by at least 13 distinct G protein-coupled receptors (GPCRs) of the type A family which includes the monoamine receptors and a combination of ligand-gated ion channels (5-HT₃) of the Cys loop family which constitutes heteropentamers. 5-HT receptors are currently divided into seven classes (5-HT₁ to 5-HT₇), based on structural, transductional and operational features. While this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity is supported by the existence of a great number of splice and editing variants for several 5-HT receptors, their possible modulation by accessory proteins and chaperones, as well as their potential to form homo or heteromers both at the GPCR and at the ligand-gated channel level.
Systematic Screening of the Serotonin Receptor 1A (5-HT1A) Gene in Chronic Tinnitus
2006, Journal of Otology
Chronic tinnitus is a highly prevalent condition and has been hypothesized to result from an innate disturbance in central nervous serotonergic transmission. Given the frequent comorbidity with major depression and anxiety, we argue that candidate genes for these disorders are likely to overlap. The present study addresses the gene encoding for the 5-HT1A receptor as a putative risk factor for tinnitus.
In 88 subjects with a diagnosis of chronic subjective tinnitus who underwent a detailed neurootological examination, the entire 5-HT1A gene was amplified using overlapping PCR products. Amplicons were custom sequenced bidirectionally and were screened for variants in multiple alignments against the human genome reference.
We identified a synonymous C>T exchange at residue 184 (Pro) in 7/88 subjects, but detected no missense variants in the population under study. Specifically, the following residues were fully conserved: 16 (Pro), 22(Gly), 28(Ile), 98 (Val), 220(Arg), 267 (Val), 273 (Gly), and 418 (Asn).
The present data count against the causation of chronic tinnitus by a change in the 5-HT1A receptor’s amino acid sequence. However, the allele frequency for the 184Pro minor allele (0.04) reached twice the frequency reported in control cohorts from the same ethnicity. Additional investigations are invited to clarify the role of the 5-HT1A polymorphism in larger samples, and to control for comorbid affective disorders.
A comparison of recent parametric neuroreceptor mapping approaches based on measurements with the high affinity PET radioligands [<sup>11</sup>C]FLB 457 and [<sup>11</sup>C]WAY 100635
2006, NeuroImage
In positron emission tomography (PET) studies, the detailed mapping of neuroreceptor binding is a trade-off between parametric accuracy and spatial precision. Logan's graphical approach is a straightforward way to quickly obtain binding potential values at the voxel level but it has been shown to have a noise-dependent negative bias. More recently suggested approaches claim to improve parametric accuracy with retained spatial resolution. In the present study, we used PET measurements on regional D₂ dopamine and 5-HT_1A serotonin receptor binding in man to compare binding potential (BP) estimates of six different parametric imaging approaches to the traditional Logan ROI-based approach which was used as a “gold standard”. The parametric imaging approaches included Logan's reference tissue graphical analysis (PILogan), its version recently modified by Varga and Szabo (PIVarga), two versions of the wavelet-based approach, Gunn's basis function method (BFM) and Gunn et al.'s recent compartmental theory-based approach employing basis pursuit strategy for kinetic modeling (called DEPICT). Applicability for practical purposes in basic and clinical research was also considered. The results indicate that the PILogan and PIVarga approaches fail to recover the correct values, the wavelet-based approaches overcome the noise susceptibility of the Logan fit with generally good recovery of BP values, and BFM and DEPICT seem to produce values with a bias dependent on receptor density. Further investigations on this bias and other phenomena revealed fundamental issues regarding the use of BFM and DEPICT on noisy voxel-wise data. In conclusion, the wavelet-based approaches seem to provide the most valid and reliable estimates across regions with a wide range of receptor densities. Furthermore, the results support the use of receptor parametric imaging in applied studies in basic or clinical research.
Cholesterol modulates ligand binding and G-protein coupling to serotonin<inf>1A</inf> receptors from bovine hippocampus
2004, Biochimica et Biophysica Acta - Biomembranes
Citation Excerpt :
Furthermore, 5-HT1A receptor levels have been shown to be increased in schizophrenia [43,44]. The 5-HT1A receptor gene has also been implicated in Tourette's syndrome, a common hereditary motor and vocal tic disorder [45]. We have earlier solubilized and partially purified the 5-HT1A receptor from bovine hippocampus [46,47] and other sources [48] in a functionally active form.
The serotonin_1A (5-HT_1A) receptor is an important member of the superfamily of seven-transmembrane domain G-protein-coupled receptors. We have examined the modulatory role of cholesterol on the ligand binding activity and G-protein coupling of the bovine hippocampal 5-HT_1A receptor by depleting cholesterol from native membranes using methyl-β-cyclodextrin (MβCD). Removal of cholesterol from bovine hippocampal membranes using varying concentrations of MβCD results in a concentration-dependent reduction in specific binding of the agonist 8-OH-DPAT to 5-HT_1A receptors. This is accompanied by alterations in binding affinity and sites obtained from analysis of binding data. Importantly, cholesterol depletion affected G-protein-coupling of the receptor as monitored by the GTP-γ-S assay. The concomitant changes in membrane order were reported by changes in fluorescence polarization of membrane probes such as DPH and TMA-DPH, which are incorporated at different locations (depths) in the membrane. Replenishment of membranes with cholesterol led to recovery of ligand binding activity as well as membrane order to a considerable extent. Our results provide evidence, for the first time, that cholesterol is necessary for ligand binding and G-protein coupling of this important neurotransmitter receptor. These results could have significant implications in understanding the influence of the membrane lipid environment on the activity and signal transduction of other G-protein-coupled transmembrane receptors.
Pharmacology of polymorphic variants of the human 5-HT<inf>1A</inf> receptor
2004, Biochemical Pharmacology
Citation Excerpt :
Recent advances in the sequencing of the human genome, and parallel studies specifically exploring the frequency and nature of SNPs have highlighted the greater than expected degree of polymorphism in the human genome [17,18]. A number of studies have documented the presence of single nucleotide polymorphisms (SNPs) within the human 5-HT1A receptor gene, which include polymorphisms that change the coding sequence of the gene (cSNPs) [19–22]. Here we have functionally analyzed these and additional potential cSNPs that were identified by surveying the patent literature and searching for nonredundant 5-HT1A coding sequences in the GenBank database (Fig. 1).
The 5-HT_1A receptor is a critical mediator of serotonergic (5-HT) function. We have identified 13 potential single nucleotide polymorphisms resulting in amino acid changes throughout the human 5-HT_1A receptor. The pharmacological profiles of these 13 polymorphic variants were then characterized using a high-throughput assay based on ligand-dependent transformation of NIH/3T3 cells. The majority of the polymorphic variants displayed wild-type pharmacological profiles in response to a panel of well-established agonists at the 5-HT_1A receptor. However, the A50V polymorphic variant, which had an alanine to valine substitution in transmembrane 1, exhibited a loss of detectable response to 5-HT. Interestingly, all other agonists tested, including buspirone, lisuride, and (+)8-OH-DPAT, exhibited efficacies similar to that of the wild-type receptor. The competitive antagonist, methiothepin, also displayed a 19-fold decrease in potency at the A50V variant receptor. However, both 5-HT and methiothepin were able to compete for [ $^{3} H$ ]WAY-100635 binding to the A50V variant with affinities similar to the wild-type receptor. Moreover, the B_max of [ $^{3} H$ ]WAY-100635 binding was 14-fold lower for the A50V variant than for the wild-type receptor. Thus, the A50V receptor variant exhibited ligand-specific functional alterations in addition to lower expression levels. These data suggest a previously unappreciated role for transmembrane 1 in mediating 5-HT response at the 5-HT_1A receptor. Furthermore, individuals that potentially harbor the A50V polymorphism might display aberrant affective behaviors and altered responses to drugs targeting the 5-HT_1A receptor.
Dyskinesias
2003, Neurological Disorders: Course and Treatment: Second Edition
This chapter describes the disorders, including various forms of involuntary activation of muscles from tonic dystonia to more phasic involuntary movements— such as— tardive dyskinesias, ballism, or tics. Although these movement disorders are generally considered of central origin because of similarities in clinical features and therapeutical approach, hemi facial spasm, a peripherally induced movement disorder. The concept of dystonia was introduced by Oppenheim in 1911 (dystonia musculorum deformans). Dystonia is defined as a syndrome of sustained and patterned muscle contractions frequently causing twisting and repetitive movements or abnormal postures. Brief muscle contractions may additionally lead to jerk like (myoclonic dystonia), or abnormal postures—such as— torticollis. Different forms of dystonia are classified depending on the age at onset, their cause, and the distribution of the body parts involved. Recent advances in the understanding of the genetics of dystonia have led to modifications of previous schemes used to classify the different causes of dystonia. As for a number of dystonic syndromes abnormal genes have been identified, it is now recommended to use the term primary for idiopathic, and secondary instead of symptomatic dystonias.

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Regular ArticleA Serotonin Receptor Gene (5HT1A) Variant Found in a Tourette's Syndrome Patient

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Regular Article
A Serotonin Receptor Gene (5HT1A) Variant Found in a Tourette's Syndrome Patient