Association of a missense change in the D2 dopamine receptor with myoclonus dystonia

Klein, Christine; Brin, Mitchell F.; Kramer, Patricia L.; Sena‐Esteves, Miguel; Leon, Deborah de; Doheny, Dana; Bressman, Susan; Fahn, Stanley; Breakefield, Xandra O.; Ozelius, Laurie J.

doi:10.1073/pnas.96.9.5173

Cited by 121 publications

(73 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Positronemission tomography (PET) studies in Lesch-Nyhan disease show reductions in [ 18 F]-DOPA uptake, and in labeling with WIN-35,428, a marker of dopamine transporter, in the basal ganglia and other regions of the brain (Ernst et al, 1996;Wong et al, 1996). Mutations in the gene that codes for the rate-limiting enzyme in dopamine metabolism, tyrosine hydroxylase, also give rise to dystonias (Knappskog et al, 1995), as do mutations within the dopamine D2 receptor gene (myoclonus-dystonia, DYT11, Klein et al, 1999), or polymorphisms within the dopamine D5 receptor gene (Placzek et al, 2001). …”

Section: The Role Of Dopamine In Dystoniamentioning

confidence: 99%

Commentary: Dopaminergic dysfunction in DYT1 dystonia

Wichmann

2008

Experimental Neurology

View full text Add to dashboard Cite

A three-base-pair deletion in the torsinA gene leads to generalized torsion dystonia (DYT1) in humans, an often devastating movement disorder in which voluntary movements are disrupted by sustained muscle spasms and abnormal limb posturing. In a recent issue of Experimental Neurology, Zhao et al. (2008) have provided a thorough behavioral, anatomic, and biochemical characterization of a mouse line that over-expresses human mutant torsinA, with particular emphasis on the possible role of dopaminergic dysfunction in these animals. This commentary provides an overview of the clinical and genetic features of the human disease and of the available transgenic mouse models for DYT1 dystonia, and discusses the evidence favoring the role of dopamine in the clinical manifestations of the disease.

show abstract

Section: The Role Of Dopamine In Dystoniamentioning

confidence: 99%

Commentary: Dopaminergic dysfunction in DYT1 dystonia

Wichmann

2008

Experimental Neurology

View full text Add to dashboard Cite

show abstract

“…For instance, mutations in two important genes in the biosynthesis of dopamine; the GTP cyclohydrolase (8)(9)(10) and tyrosine hydroxylase genes (11)(12), were found in patients with doparesponsive dystonia. Similarly, a mutation in the dopamine D2 receptor (D2DAR) was associated with myoclonus dystonia (13). Consistent with a potential role for the dopamine system in dystonia, the torsinA gene is expressed at high levels in dopamine neurons of the substantia nigra (14)(15)(16).…”

mentioning

confidence: 96%

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated ΔE-torsinA mutant

Torres

Sweeney²,

Beaulieu³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

172

199

View full text Add to dashboard Cite

Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of one glutamic acid in the carboxyl terminus of a protein named torsinA. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wild-type protein. Although there is increasing evidence that dysfunction of the dopamine system is implicated in the development of EOTD, the biological function of torsinA and its relation to dopaminergic neurotransmission has remained unexplored. Here, we show that torsinA can regulate the cellular trafficking of the dopamine transporter, as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsinA. The dystonia-associated torsinA deletion mutant (⌬E-torsinA) did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in ⌬E-torsinA reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of wild-type torsinA through a mechanism presumably involving association of wild-type and mutant torsinA. Taken together, our results provide evidence for a functional role for torsinA and a loss of function and a dominant-negative phenotype of the ⌬E-torsinA mutation. These properties may contribute to the autosomal dominant nature of the condition. deletion mutant ͉ cell surface ͉ endoplasmic reticulum ͉ transmembrane ͉ polytopic

show abstract

“…Because new results have revealed that SSTR5 and DRD2 form functional heterodimers [Rocheville et al, 2000], we also checked the Danish and French cases for the following five mutations in the DRD2 gene: Val96Ala [Gejman et al, 1994], Val154Ile [Klein et al, 1999], Pro310Ser [Gejman et al, 1994], Ser311Cys [Itokawa et al, 1993], and Thr351Ala (available via the NCBI SNP database (http://www.ncbi.nlm.nih.gov/SNP/), SNP ID rs1110977ref). Not surprisingly, we were unable to find any of the five DRD2 missense mutations among cases since they are all very rare.…”

Section: Discussionmentioning

confidence: 99%

Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene in patients with autism

Lauritsen¹,

Nyegaard

Betancur

et al. 2003

American J of Med Genetics Pt B

View full text Add to dashboard Cite

Infantile autism is a pervasive developmental disorder with a strong genetic component. The mode of inheritance appears to be complex and no specific susceptibility genes have yet been identified. Chromosome 16p13.3 may contain a susceptibility gene based on findings from genome scans and reports of chromosome abnormalities in individuals with autism. The somatostatin receptor 5 (SSTR5) gene is located on chromosome 16p13.3 and is thus a positional candidate gene for autism. SSTR5 may also be a functional candidate gene for autism because somatostatin inhibits growth hormone secretion, and increased growth hormone response has been reported in some individuals with autism. Moreover, the somatostatinergic system interacts with the dopaminergic system, which has been hypothesized to be involved in the etiology of autism; in particular, somatostatin secretion is regulated by dopamine, and the dopamine D2 receptor and the SSTR5 receptor interact to form a receptor complex with enhanced functional activity. In the present study, we tested whether the alleles of twelve new single nucleotide polymorphisms (SNPs) in the SSTR5 gene were preferentially transmitted, using the transmission disequilibrium test (TDT) in a sample of 79 trios with autism (18 from Denmark and 61 from France). Furthermore, we combined four missense SNPs into haplotypes and searched for preferential transmission using the program TRANSMIT. No significant preferential transmission of the alleles and haplotypes of the twelve SNPs was found. Our results do not suggest the SSTR5 gene as a susceptibility gene for autism.

show abstract

Association of a missense change in the D2 dopamine receptor with myoclonus dystonia

Cited by 121 publications

References 36 publications

Commentary: Dopaminergic dysfunction in DYT1 dystonia

Commentary: Dopaminergic dysfunction in DYT1 dystonia

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated ΔE-torsinA mutant

Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene in patients with autism

Contact Info

Product

Resources

About