The Open Neurology Journal




ISSN: 1874-205X ― Volume 14, 2020

DJ-1 Mutations are Rare in a Swedish Parkinson Cohort



Anna Anvret 1, Jeff G Blackinton 1, 2, Marie Westerlund 1, Caroline Ran 1, Olof Sydow 3, Thomas Willows 3, Anna Håkansson 4, Hans Nissbrandt 4, Andrea Carmine Belin*, 1
1 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
2 Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA
3 Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
4 Department of Pharmacology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Abstract

Mutations in the PARK7 gene, DJ-1, have been reported to cause early-onset and familial Parkinson’s disease (PD). The function of DJ-1 and how it contributes to the development of the disease is not clear today, but several studies report that DJ-1 is responsive to oxidative stress and important for the maintenance of mitochondria. We have screened three coding regions of DJ-1 (exon 2, 5 and 7) in a Swedish Parkinson cohort. The Swedish PD material consisted of 67 patients with a self reported positive family history of PD and 77 patients with early-onset of disease (≤50 years old). We detected two patients with the previously reported synonymous mutation, Ala167Ala (c.501A>G, rs71653621), in exon 7. No Ala167Ala carriers were identified among 213 neurologically healthy Swedish controls. Mechanisms by which the synonymous Ala167Ala mutation can have consequences are unknown. It may affect the mRNA stability, secondary structure of mRNA, synthesis, turnover, protein folding and function. We could show a 1.3% decrease in DJ-1 mRNA folding energy in the A<G substituted sequence compared to the wild type sequence in silico, suggesting a possible small effect of Ala167Ala on DJ-1 gene function. This is the first report on an identified DJ-1 mutation in Swedish PD patients. Our results, in combination with those of previous studies, strengthen the hypothesis that alterations in DJ-1 are not a common cause of familial and early-onset PD world-wide.

Keywords: PARK7, mitochondria, mutation, oxidative stress.


Article Information


Identifiers and Pagination:

Year: 2011
Volume: 5
First Page: 8
Last Page: 11
Publisher Id: TONEUJ-5-8
DOI: 10.2174/1874205X01105010008

Article History:

Received Date: 22/10/2010
Revision Received Date: 10/12/2010
Acceptance Date: 3/1/2011
Electronic publication date: 22/3/2011
Collection year: 2011

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© Anvret et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Neuroscience, Retzius väg 8, B2:4, Karolinska Institutet, 171 77 Stockholm, Sweden; Tel: +46-8-524 870 51; Fax: +46-8-323 742; E-mail: andrea.carmine.belin@ki.se





INTRODUCTION

Parkinson’s disease (PD) is a neurodegenerative disorder caused mainly by progressive loss of dopamine neurons in substantia nigra pars compacta. Pathways proposed to trigger onset of PD include oxidative stress and dysfunction of mitochondria [1Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson's disease Nature 1998; 395: 451-2.]. The PARK7 gene, DJ-1, has been reported to be responsive to oxidative stress and important for the maintenance of mitochondria [2Canet-Aviles RM, Wilson MA, Miller DW, et al. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization Proc Natl Acad Sci USA 2004; 101: 9103-8.,3Kahle PJ, Waak J, Gasser T. DJ-1 and prevention of oxidative stress in Parkinson's disease and other age-related disorders Free Radic Biol Med 2009; 47: 1354-61.]. DJ-1 was originally identified and described as an oncogene [4Nagakubo D, Taira T, Kitaura H, et al. DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras Biochem Biophys Res Commun 1997; 231: 509-13.] and the 189 amino acid protein is highly conserved across species [5Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism Science 2003; 299: 256-9.]. The DJ-1 protein is abundantly expressed throughout the body and in the normal human brain it is moderately expressed in neurons and in astrocytes throughout the CNS [6Bandopadhyay R, Kingsbury AE, Cookson MR, et al. The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease Brain 2004; 127: 420-30.,7Galter D, Westerlund M, Belin AC, Olson L. DJ-1 and UCH-L1 gene activity patterns in the brains of controls, Parkinson and schizophrenia patients and in rodents Physiol Behav 2007; 92: 46-53.]. Oxidative modifications of DJ-1 have been reported in brain tissue from patients with sporadic PD and Alzheimer’s disease compared to controls [8Choi J, Sullards MC, Olzmann JA, et al. Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases J Biol Chem 2006; 281: 10816-24.]. It has been suggested that DJ-1 protect neurons against oxidative stress by acting as a redox-dependent chaperone [9Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL. The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein J Mol Biol 2006; 356: 1036-48.]. The protein is normally found in the cytoplasm and oxidative stress promotes relocation to mitochondria where it protects against mitochondrial toxins [2Canet-Aviles RM, Wilson MA, Miller DW, et al. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization Proc Natl Acad Sci USA 2004; 101: 9103-8.,10Zhang L, Shimoji M, Thomas B, et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis Hum Mol Genet 2005; 14: 2063-73.]. DJ-1 can bind RNA in an oxidative-dependent manner and the DJ-1/RNA complex dissociates after oxidative stress [11Hod Y, Pentyala SN, Whyard TC, El-Maghrabi MR. Identification and characterization of a novel protein that regulates RNA-protein interaction J Cell Biochem 1999; 72: 435-4.,12van der Brug MP, Blackinton J, Chandran J, et al. RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways Proc Natl Acad Sci USA 2008; 105: 10244-9.]. Structural studies of DJ-1 have suggested oxidation of Cysteine at residue 106 to be essential for DJ-1 to exert its full activities [3Kahle PJ, Waak J, Gasser T. DJ-1 and prevention of oxidative stress in Parkinson's disease and other age-related disorders Free Radic Biol Med 2009; 47: 1354-61.]. However it remains to be shown how oxidation of Cys106 leads to antioxidative and/or cytoprotective effects through conformational changes and how PD associated DJ-1 mutations affect these processes.

In 2001 the PARK7 locus on chromosome 1p36 was linked to a family with autosomal recessive early-onset parkinsonism (AREP) in the Netherlands [13van Duijn CM, Dekker MC, Bonifati V, et al. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36 Am J Hum Genet 2001; 69: 629-34.]. The following year the same locus was linked to a family with AREP in Italy [14Bonifati V, Breedveld GJ, Squitieri F, et al. Localization of autosomal recessive early-onset parkinsonism to chromosome 1p36 (PARK7) in an independent dataset Ann Neurol 2002; 51: 253-6.]. Two mutations in DJ-1 were later reported to cosegregate with disease, a 14kb deletion in the Dutch PD family and a Leu166Pro substitution in the Italian PD family, and both lead to loss of gene function [5Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism Science 2003; 299: 256-9.]. The DJ-1 mutations are recessively inherited and result in PD with early-onset, overall mutations identified to date are rare, causing ~1% of the PD cases world-wide and no mutations have been reported in Swedish PD cases [15Lockhart PJ, Lincoln S, Hulihan M, et al. DJ-1 mutations are a rare cause of recessively inherited early onset parkinsonism mediated by loss of protein function J Med Genet 2004; 41: e22.]. In the Caucasian PD population the majority of DJ-1 mutations leading to changes in the amino acid sequence have been found in exons 2, 5 and 7 [16Nuytemans K, Theuns J, Cruts M, Van BC. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update Hum Mutat 2010; 31: 763-80.]. We therefore sequenced these exons in a Swedish Parkinson cohort to search for known and new variable sites.

MATERIAL AND METHODS

Subjects

Exons 2, 5 and 7 and the exon/intron borders of DJ-1 were sequenced in a Swedish PD material consisting of 144 individuals (mean age 64.3 years, 56.9% men). 77 of the PD patients had an early disease onset (≤50 years old) and 67 of the patients had a self reported positive family history of PD in one or more first-, second- or third-degree relatives (15 of these patients had early-onset as well). 66 of the early-onset cases have previously been investigated for possible changes in copy numbers in exon 1, 3, 5 and 7 of DJ-1 although no aberrations were detected [17Håkansson A, Belin AC, Stiller C, et al. Investigation of genes related to familial forms of Parkinson's disease--with focus on the Parkin gene Parkinsonism Relat Disord 2008; 14: 520-2.]. These patients were screened for Parkin point mutations and Parkin, α-Synuclein, UCH-L1 and PINK1 exon copy number aberration as well. No known PD causing Parkin mutation or copy number aberration was found. Control subjects consisted of 213 neurologically healthy participants from the Stockholm area (mean age 75.8 years, 41.3% men). The material was obtained after informed oral and written consent and approval of the local ethics committee at Karolinska Institutet and University of Gothenburg. All PD subjects met the United Kingdom Parkinson's Disease Society Brain Bank Criteria for PD except that more than one affected relative was allowed [18Daniel SE, Lees AJ. Parkinson's Disease Society Brain Bank, London: overview and research J Neural Transm Suppl 1993; 39: 165-72.]. DNA was extracted from blood according to standard protocol.

Sequencing

Samples from PD patients were analyzed with automated capillary sequencing. Polymerase chain reaction (PCR) was carried out using Taq DNA polymerase and the following primer sequences: exon 2 forward primer 5´-TCTCAGGG TTGCAATGAAAG-3´; reverse primer 5´-AAGCGTTAA ATGTGAGCAGTG-3´, exon 5 forward primer 5´-AAATAGGTCAGAGAGCTTGTGG-3´; reverse primer 5´-TCAAACCATCGAATGAAAGG-3´ and exon 7 forward primer 5´-ACAGTGTTGGGTTTATATGCTG-3´; reverse primer 5´-GGACAGCGACTTCTGAACAC-3´. 40 cycles were run at 95°C for 45 s, 56°C for 40 s and 72°C for 1 min followed by 7 min terminal elongation at 72°C. The PCR products were 337 bp (exon 2), 258 bp (exon 5) and 378 bp (exon 7) of the DJ-1 gene. Purification of the amplified fragment was performed by using QIAquick® PCR Purification kit (Qiagen, Hilden, Germany). The isolated DNA fragments were sequenced using a DTCS kit followed by automated capillary gel electrophoresis (CEQ 2000 system, Beckman Coulter Inc., Fullerton, CA, USA), following the provider’s instruction.

Pyrosequencing

To specifically screen neurologically healthy controls for the Ala167Ala mutation in exon 7 we used pyrosequencing [19Ronaghi M, Uhlen M, Nyren P. A sequencing method based on real-time pyrophosphate Science 1998; 281: 363-5.] and the following primer sequences; forward primer 5´-AGACGGCCTGATTCTTACAAGC-3´; reverse primer 5´-GGCCTGTTTCTCTAAGTGATCG-3´ and sequencing primer 5´-CTTCGAGTTTGCGC-3´. The reverse primer was biotinylated at the 5´-end. Positive controls for the Ala167Ala mutation were used in the pyrosequencing assay to guarantee accuracy of the method as well as water controls. PCR was carried out with Taq DNA polymerase to amplify a 175 bp fragment. 45 cycles were run at 95°C for 20 s, 57°C for 20 s and 72°C for 30 s followed by 7 min terminal elongation at 72°C, after which the biotinylated PCR product was immobilized on streptavidin-coated beads by mixing at 2500 rpm for 10 min at room temperature according to manufacturer’s instructions. The immobilized DNA template was then captured onto filter probes (PyroMark Vacuum Prep Tool, Biotage AB, Uppsala, Sweden). The filter probes were flushed with 70% ethanol, denaturation solution, washing buffer and the single-stranded template was annealed to a reverse sequencing primer at 80°C for 2 min followed by cooling to room temperature. All solutions used in sample preparation were prepared according to manufacturer’s instructions (Biotage AB, Uppsala, Sweden). Samples were analyzed on an automated pyrosequencer using a PSQ 96 System together with single SNP Software and SNP Reagent Kits (Biotage AB, Uppsala, Sweden).

Prediction of mRNA Secondary Structure

To evaluate the possible effect of the identified Ala167Ala mutation on the DJ-1 mRNA level, the secondary structure was predicted using the publicly available online software mfold version 3.2 [20Mathews DH, Sabina J, Zuker M, Turner DH. Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure J Mol Biol 1999; 288: 911-40.,21Zuker M. Mfold web server for nucleic acid folding and hybridization prediction Nucleic Acids Res 2003; 31: 3406-15.]. Partial DJ-1 mRNA sequences of 141 nucleotides including flanking sequences (70 nucleotides) on either side of the mutation were analyzed and compared to the wild type sequence.

RESULTS

In 144 PD cases we identified the synonymous mutation, Ala167Ala (c.501A>G, rs71653621), in exon 7 of DJ-1 in two PD patients (Fig. 1 and Table 1). No Ala167Ala carriers were identified among the 213 neurologically healthy Swedish controls. To test whether the synonymous Ala167Ala substitution has a possible effect on the secondary structure of DJ-1 mRNA we performed a structure analysis in silico. Our results indicated a small decrease in mRNA folding energy (1.3%) in the A>G substituted sequence compared to the wild type sequence (Table 2).

Fig. (1)

Results from automated capillary sequencing of exon 7 in DJ-1 including the Ala167Ala (c.501A>G, rs71653621) mutation using a reverse sequencing primer (T>C). a) A homozygous wild type (WT) T/T, Ala167Ala carrier and b) a heterozygous (Het) T/C, Ala167Ala carrier.



Table 1

Patient Information on the Two Individuals with Parkinson’s Disease (PD) Heterozygous for the DJ-1 Mutation Ala167Ala (c.501A>G, rs71653621) in Exon 7




Table 2

In Silico mRNA Folding Energy (kcal/mol) for the Wild Type (WT) and Mutated (MUT) Ala167Ala DJ-1 Sequences




DISCUSSION

The number of DJ-1 mutations described today is low and they account for only a few PD cases in different populations [16Nuytemans K, Theuns J, Cruts M, Van BC. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update Hum Mutat 2010; 31: 763-80.]. In the present study, we have searched for mutations in exon 2, 5 and 7 and in the exon/intron borders of DJ-1, since variations have been reported in these regions [22Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW. The role of pathogenic DJ-1 mutations in Parkinson's disease Ann Neurol 2003; 54: 283-6.]. We detected a heterozygote Ala167Ala mutation in two out of 144 Swedish PD patients, but no Ala167Ala carriers were identified among the 213 neurologically healthy controls. This is the first report on DJ-1 mutations identified in a Swedish PD material. The Ala167Ala mutation was previously identified in a PD patient (homozygote carrier) from the United Kingdom and in a patient from a North American material with Caucasian/Hispanic origin (heterozygote carrier) [22Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW. The role of pathogenic DJ-1 mutations in Parkinson's disease Ann Neurol 2003; 54: 283-6.,23Pankratz N, Pauciulo MW, Elsaesser VE, et al. Mutations in DJ-1 are rare in familial Parkinson disease Neurosci Lett 2006; 408: 209-13.]. One of the Swedish Ala167Ala carriers was diagnosed with Alzheimer’s disease as well (Table 1), which is in agreement with the reports that DJ-1 has been implicated in Alzheimer’s disease [8Choi J, Sullards MC, Olzmann JA, et al. Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases J Biol Chem 2006; 281: 10816-24.]. Mechanisms by which the synonymous Ala167Ala mutation may have consequences on the protein level and predispose to disease are not well understood. The DJ-1 protein has been suggested to act in multiple pathways and hypothesized that loss of the protective function of DJ-1 in dopaminergic neurons can lead to neurodegeneration [24Lev N, Ickowicz D, Barhum Y, et al. DJ-1 protects against dopamine toxicity J Neural Transm 2009; 116: 151-60.]. Several possibilities have been suggested for synonymous mutations including alterations of mRNA stability, secondary structure, transcriptional activity, or changes in protein synthesis, folding, levels, turnover and/or function [25Parmley JL, Hurst LD. How do synonymous mutations affect fitness? Bioessays 2007; 29: 515-9.]. We found a small decrease in mRNA folding energy (1.3%) comparing the mutated Ala167Ala sequence with the wild type sequence, suggesting a possible effect of Ala167Ala on DJ-1 gene function [26Bartoszewski RA, Jablonsky M, Bartoszewska S, et al. A synonymous single nucleotide polymorphism in DeltaF508 CFTR alters the secondary structure of the mRNA and the expression of the mutant protein J Biol Chem 2010; 285: 28741-8.]. However, no strong conclusions can be drawn from the artificial conditions used for modeling secondary structures in silico.

The frequency of DJ-1 mutations has been reported to vary among PD populations with different ethnic origin, Caucasian: 0.91%, Asian: 3.03%, Arab: 0.74% and Ashkenazi Jews: 1.96% and copy number variations in DJ-1 have so far only been reported in the Caucasian PD population (0.54%) [16Nuytemans K, Theuns J, Cruts M, Van BC. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update Hum Mutat 2010; 31: 763-80.]. We found the Ala167Ala mutation in two PD patients in our Swedish cohort, but no other genetic variant in any of the three investigated exons. The observed DJ-1 mutation frequency (1.4%) is in agreement with findings in other Caucasian PD populations.

CONCLUSION

This is the first report on a DJ-1 mutation identified in Swedish PD patients. Based on the results of the screening in our Swedish cohort as well as the results from other studies, it appears clear that mutations in DJ-1 are a rare cause of familial and early-onset PD world-wide.

ACKNOWLEDGEMENTS

We would like to thank Professor Laura Fratiglioni for providing us with control samples from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) project and Doctor Fengqing Xiang for excellent technical assistance. The study was supported by the Swedish Research Council, the Swedish Brain Foundation, Karolinska Institutet Funds, the Swedish Parkinson Foundation, Swedish Brain Power and Åhlen´s Foundation.

REFERENCES

[1] Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson's disease Nature 1998; 395: 451-2.
[2] Canet-Aviles RM, Wilson MA, Miller DW, et al. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization Proc Natl Acad Sci USA 2004; 101: 9103-8.
[3] Kahle PJ, Waak J, Gasser T. DJ-1 and prevention of oxidative stress in Parkinson's disease and other age-related disorders Free Radic Biol Med 2009; 47: 1354-61.
[4] Nagakubo D, Taira T, Kitaura H, et al. DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras Biochem Biophys Res Commun 1997; 231: 509-13.
[5] Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism Science 2003; 299: 256-9.
[6] Bandopadhyay R, Kingsbury AE, Cookson MR, et al. The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease Brain 2004; 127: 420-30.
[7] Galter D, Westerlund M, Belin AC, Olson L. DJ-1 and UCH-L1 gene activity patterns in the brains of controls, Parkinson and schizophrenia patients and in rodents Physiol Behav 2007; 92: 46-53.
[8] Choi J, Sullards MC, Olzmann JA, et al. Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases J Biol Chem 2006; 281: 10816-24.
[9] Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL. The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein J Mol Biol 2006; 356: 1036-48.
[10] Zhang L, Shimoji M, Thomas B, et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis Hum Mol Genet 2005; 14: 2063-73.
[11] Hod Y, Pentyala SN, Whyard TC, El-Maghrabi MR. Identification and characterization of a novel protein that regulates RNA-protein interaction J Cell Biochem 1999; 72: 435-4.
[12] van der Brug MP, Blackinton J, Chandran J, et al. RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways Proc Natl Acad Sci USA 2008; 105: 10244-9.
[13] van Duijn CM, Dekker MC, Bonifati V, et al. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36 Am J Hum Genet 2001; 69: 629-34.
[14] Bonifati V, Breedveld GJ, Squitieri F, et al. Localization of autosomal recessive early-onset parkinsonism to chromosome 1p36 (PARK7) in an independent dataset Ann Neurol 2002; 51: 253-6.
[15] Lockhart PJ, Lincoln S, Hulihan M, et al. DJ-1 mutations are a rare cause of recessively inherited early onset parkinsonism mediated by loss of protein function J Med Genet 2004; 41: e22.
[16] Nuytemans K, Theuns J, Cruts M, Van BC. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update Hum Mutat 2010; 31: 763-80.
[17] Håkansson A, Belin AC, Stiller C, et al. Investigation of genes related to familial forms of Parkinson's disease--with focus on the Parkin gene Parkinsonism Relat Disord 2008; 14: 520-2.
[18] Daniel SE, Lees AJ. Parkinson's Disease Society Brain Bank, London: overview and research J Neural Transm Suppl 1993; 39: 165-72.
[19] Ronaghi M, Uhlen M, Nyren P. A sequencing method based on real-time pyrophosphate Science 1998; 281: 363-5.
[20] Mathews DH, Sabina J, Zuker M, Turner DH. Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure J Mol Biol 1999; 288: 911-40.
[21] Zuker M. Mfold web server for nucleic acid folding and hybridization prediction Nucleic Acids Res 2003; 31: 3406-15.
[22] Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW. The role of pathogenic DJ-1 mutations in Parkinson's disease Ann Neurol 2003; 54: 283-6.
[23] Pankratz N, Pauciulo MW, Elsaesser VE, et al. Mutations in DJ-1 are rare in familial Parkinson disease Neurosci Lett 2006; 408: 209-13.
[24] Lev N, Ickowicz D, Barhum Y, et al. DJ-1 protects against dopamine toxicity J Neural Transm 2009; 116: 151-60.
[25] Parmley JL, Hurst LD. How do synonymous mutations affect fitness? Bioessays 2007; 29: 515-9.
[26] Bartoszewski RA, Jablonsky M, Bartoszewska S, et al. A synonymous single nucleotide polymorphism in DeltaF508 CFTR alters the secondary structure of the mRNA and the expression of the mutant protein J Biol Chem 2010; 285: 28741-8.

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