0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Heterogeneous Phenotype in a Family With Compound Heterozygous Parkin Gene Mutations FREE

Hao Deng, PhD; Wei-Dong Le, MD, PhD; Christine B. Hunter, RN; William G. Ondo, MD; Yi Guo, MS; Wen-Jie Xie, MD; Joseph Jankovic, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, Baylor College of Medicine, Houston, Tex (Drs Deng, Le, Ondo, Xie, and Jankovic and Ms Hunter); and School of Medical Technology and Information, Central South University, Changsha, China (Ms Guo).


Arch Neurol. 2006;63(2):273-277. doi:10.1001/archneur.63.2.273.
Text Size: A A A
Published online

Background  Mutations in the parkin gene (PRKN) cause autosomal recessive early-onset Parkinson disease (EOPD).

Objective  To investigate the presence of mutations in the PRKN gene in a white family with EOPD and the genotype-phenotype correlations.

Design  Twenty members belonging to 3 generations of the EOPD family with 4 affected subjects underwent genetic analysis. Direct genomic DNA sequencing, semiquantitative polymerase chain reaction, real-time quantitative polymerase chain reaction, and reverse-transcriptase polymerase chain reaction analyses were performed to identify the PRKN mutation.

Results  Compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene were identified in 4 patients with early onset (at ages 30-38 years). Although heterozygous T240M and homozygous EX 5_6 del mutations in the PRKN gene have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. The phenotype of patients was that of classic autosomal recessive EOPD characterized by beneficial response to levodopa, relatively slow progression, and motor complications. All heterozygous mutation carriers (T240M or EX 5_6 del) and a 56-year-old woman who was a compound heterozygous mutation carrier (T240M and EX 5_6 del) were free of any neurological symptoms.

Conclusions  Compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene were found to cause autosomal recessive EOPD in 4 members of a large white family. One additional member with the same mutation, who is more than 10 years older than the mean age at onset of the 4 affected individuals, had no clinical manifestation of the disease. This incomplete penetrance has implications for genetic counseling, and it suggests that complex gene-environment interactions may play a role in the pathogenesis of PRKN EOPD.

Figures in this Article

Early-onset Parkinson disease (EOPD), beginning before 50 years of age, is clinically and genetically heterogeneous.1 At least 5 genes have been identified as causal genes for EOPD, including α-synuclein (PARK1),2 parkin (PRKN, PARK2),3DJ-1(PARK7),4 PTEN-induced kinase 1 (PINK1, PARK6),5 and leucine-rich repeat kinase 2 (LRRK2, PARK8).6,7 Homozygous and compound heterozygous mutations in the PRKN gene are responsible for 49% of familial EOPD and 18% of sporadic EOPD,8 and at least 109 different mutations have been identified in the Human Gene Mutation Database, including 38 nonsense/missense mutations and 38 gross deletions (available at: http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html), whereas mutations in late-onset cases are rare. We describe herein a large family with EOPD caused by compound heterozygous mutations in the PRKN gene: a missense mutation (T240M) and a gross deletion (EX 5_6 del; deletion of exons 5 and 6). This family draws attention to the broad spectrum of phenotypes in the PRKN group of EOPD.

PEDIGREE, PATIENTS, AND HEALTHY CONTROL SUBJECTS

A 3-generation, 20-member family in which 4 members had EOPD (the mother is Irish American and the father is Dutch and American Indian) underwent screening for PRKN mutations. They were compared with 208 patients with PD, including 106 with EOPD (male-female ratio, 55:51; mean ± SD onset age, 40.2 ± 7.2 years) and 102 with late-onset PD (male-female ratio, 52:50; mean ± SD onset age, 63.2 ± 8.7 years), and 134 healthy control subjects (male-female ratio, 69:65; mean ± SD age, 57.2 ± 11.2 years). Patients were diagnosed as having PD according to common diagnostic criteria.9 This study was approved by the Baylor College of Medicine Institutional Review Board, Houston, Tex, and all participants gave signed informed consent.

GENETIC ANALYSIS

Genomic DNA was isolated from lymphocytes using standard methods. Polymerase chain reaction (PCR) amplification of the PRKN gene was performed with the use of a thermocycler system (MyCycle; Bio-Rad Laboratories, Hercules, Calif) for 32 cycles at 95°C for 45 seconds, 58°C for 45 seconds, and 72°C for 45 seconds, for 100 ng of genomic DNA, and 10-pmol primers were used in a 25-μL reaction volume (HotStar Master Mix kit; Qiagen, Amsterdam, the Netherlands). The primers used for PCR amplification cover all coding regions and intron/exon boundaries of the PRKN gene (Table 1). The PCR products were sequenced bidirectionally using a genetic analyzer (ABI3700; Applied Biosystems, Foster City, Calif).

To determine the frequency of T240M or T240R mutations in patients with PD and in healthy controls, PCR-restriction fragment length polymorphism was conducted using the primer pair 5′-TAGAGGAAAAATGAGCAGCCGGGATC-3′ and 5′-CTATTTTTAGATCCTTACCTGACCTCTGTGC-3′. The base mismatch is underlined.

The 2-μL PCR products were digested with HpyCH4 IV restriction enzyme at 37°C overnight and resolved on 6% polyacrylamide gel. The T240M or T240R cannot be digested by HpyCH4 IV, resulting in an uncut fragment of 192 base pairs, whereas the wild-type allele can be digested into 159- and 33-base pair fragments.

Semiquantitative PCR was used for quantification of the 12 exon regions of the PRKN genomic DNA using primers (Table 1); exon 6 was also detected by real-time quantitative PCR.10,11 The glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) was amplified as a reference for quantification of the PRKN genomic DNA. The dose of the PRKN exons relative to GAPDH and normalized to control DNA was determined using the 2−ΔΔCt method12:

Ct = [CtPRKN (unknown sample) − CtGAPDH (unknown sample)] − [CtPRKN (calibrator sample) − CtGAPDH (calibrator sample)],

where Ct indicates the threshold cycle.

The PRKN and GAPDH real-time PCR probes were labeled with fluorescent dyes 6-FAM and 5-TexRed, respectively, at the 5′ end and with MGB (nonfluorescent quencher dye) at the 3′ end. In brief, 10 ng of genomic DNA was amplified in a total volume of 15 μL containing 5 pmol of each primer using a real-time PCR machine (iCycler IQ; Bio-Rad Laboratories). For evaluation of our assay, we used samples with LRRK2 R1441G and G2019S mutations as negative controls.7 All experiments were performed and were accepted only when the standard deviation was less than 10% of the calculated mean concentrations. Gene dosage alternations were confirmed after triple analysis.13 The sequences of the primers are 5′-AACATCAGTAGCTTTGCACCTG-3′ for PRKN6F; 5′-GGGGGAGTGATGCTATTTTT-3′ for PRKN6R; 5′-CAAATAGTCGGAACATCACTTGC-3′ for PRKN probe; 5′-ATTCCACCCATGGCAAATT-3′ for GAPDH-F; 5′-AGCCACACCATCCTAGTT-3′ for GAPDH-R; and 5′-CAAGCTTCCCGTTCTCAGCC-3′ for GAPDH probe.

To determine the deletion of the PRKN gene changes per messenger RNA (mRNA) splice, lymphocytes from peripheral blood were isolated from the patients and total RNA was extracted with TRIZOL reagent (Invitrogen, Carlsbad, Calif). The complementary DNA (cDNA) synthesis was completed as per the instructions of the cDNA synthesis kit (Iscript; Bio-Rad Laboratories) using 1 μg of total RNA. Polymerase chain reaction amplification from exon 1 to exon 11 was conducted using paired primers 5′-CACCTACCCAGTGACCATGA-3′ for forward primer cPRKN1-11F and 5′-ACAGGGCTTGGTGGTTTTCT-3′ for reverse primer cPRKN1-11R. The thermocycling profile was a 3-step PCR (94°C for 1.5 minutes, 58°C for 1.5 minutes, and 72°C for 2.5 minutes) for 32 cycles. We used 1 μL of the first reverse-transcriptase PCR products as a template for second amplification with paired primers (5′-TGACCAGTTGCGTGTGATTT-3′ for cPRKN2-11F and 5′-GGTTTCTTTGGAGGCTGCTT-3′ for cPRKN2-11R) and denatured the PCR products initially at 95°C followed by 28 thermocycles of 1.5 minutes at 94°C, 1.5 minutes at 60°C, 2 minutes at 72°C, and a final elongation of 5 minutes at 72°C. The PCR products were analyzed by gel purification and sequencing.

To determine the T240M change at the mRNA level, the transcribed PRKN fragment from exon 6 to exon 11 was amplified using paired primers (for cPRKN6F, 5′-CCCACCTCTGACAAGGAAAC-3′, and cPRKN1-11R) and a second amplification with paired primers (for PRKN6F and cPRKN2-11R) and sequencing.

The 4 patients from this white pedigree had typical EOPD, with age at onset of 30 to 38 years (mean age, 34.5 years). The patients had a beneficial response to levodopa, relatively slow progression of the disease, and marked motor and nonmotor fluctuations, all of which are typically present in patients with the PRKN mutations. Direct sequencing of the PRKN gene identified a C>T (NT_007422, nt 754455) substitution in exon 6 (Figure 1A), changing a threonine codon (ACG) to a methionine codon (ATG) at amino acid position 240 (T240M), rather than changing the mRNA splice site (predicted by http://hgsc.bcm.tmc.edu). The mRNA sequence was also changed by the reverse-transcriptase PCR and sequencing assay. This mutation was absent in 208 unrelated patients with PD and 134 healthy controls. Five healthy family members were heterozygous for the T240M mutation (age, 22-77 years; mean age, 38.8 years).

Place holder to copy figure label and caption
Figure 1.

Sequencing analysis of the parkin gene (PRKN). A, C>T (NT_007422, nt 754455; T240M) substitution in exon 6 in the PRKN gene (genomic DNA). The arrow shows the nucleotide mutation. B, Abnormal splice (EX 5_6 del) in the PRKN gene (complementary DNA).

Graphic Jump Location

Semiquantitative and quantitative PCR showed the deletion of exons 5 and 6 in the PRKN gene in this pedigree (Figure 2). To evaluate the change of the mRNA splice, we conducted nest reverse-transcriptase PCR to obtain the abnormal splice and identified the EX 5_6 del mutation in complementary RNA (Figure 1B). All 4 patients harbored the compound heterozygous mutations (T240M and EX 5_6 del) (Table 2), but a 56-year-old woman (II:1 in Figure 2) with the compound heterozygous mutations had no parkinsonian features. The heterozygous EX 5_6 del mutation was present in 10 healthy family members (age range, 13-75 years; mean age, 34.1 years).

Place holder to copy figure label and caption
Figure 2.

The early-onset Parkinson disease (EOPD) pedigree with the compound heterozygous mutations of the parkin gene (PRKN) (T240M and EX 5_6 del). The sex of some family members has been masked for confidentiality reasons. Years indicate present age. D indicates the allele for the EX 5_6 del mutation; M, the allele for the T240M mutation; W, wild-type allele; arrow, the proband; circles, women; filled symbols, individuals manifesting PD; and squares, men.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Clinical Characteristics of Patients With PRKN Mutations

The PRKN gene (PARK2) was mapped to chromosome 6q34 and encodes an E3 ubiquitin-proteasome system. It contains 12 exons spanning about 1.4 centimorgans and encodes a 466–amino acid protein. Parkin protein appears to have 6 phosphorylation sites (3 sites in exon 3, 1 in exon 5, and 2 in exon 6) for casein kinase II, a serine or threonine kinase that is found in the nucleus and cytoplasm of eukaryotic cells and has been implicated to play roles in regulating various cellular functions.14 Mutations in this gene account for half of familial cases of EOPD.

We identified compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene in a large white EOPD pedigree. Patients in this family began to have symptoms in their fourth decade of life, typical of PRKN EOPD. Our cases also share similar clinical features to other PRKN cases, including symptoms at disease onset, beneficial response to levodopa, and the occurrence of levodopa-related motor complications.

The T240M mutation, which presumably eliminates a phosphorylation site for casein kinase II, was found in a patient with late-onset onset PD from North America, and a homozygous T240R mutation in PRKN was previously reported in a Turkish family with EOPD,15,16 indicating that this gene site contains an important functional domain of the parkin protein. Expression of parkin, but not its T240R mutant, significantly alleviated detrimental effects of the misfolded dopamine transporter, indicating that the 240–amino acid position is very important for the maintenance of normal parkin protein function.17 Among 38 known nonsense/missense mutations in the PRKN gene, 3 nucleotides may be substituted by at least 2 different nucleotides, resulting in 2 mutated amino acids, including T240, which indicates that this position is highly liable to produce mutations. The T240M and T240R mutations were not present in 208 unrelated patients with PD or 134 healthy controls, suggesting that they are indeed mutations rather than polymorphisms, as they seem to be rare in general population. Three alternative splicing variants (NM_004562, NM_013987, and NM_013988) of the PRKN gene were described in the literature, and each of them contains exon 6.

To explore the possibility of deletions or multiplications of 1 or more exons, we conducted gene dose studies and found the deletion of exons 5 and 6 of the PRKN gene in this pedigree. Homozygous deletion of exons 5 and 6 was previously found in 2 non–North American patients with EOPD by genome DNA analysis, but the status of the transcripts was unknown.13 We found that EX 5_6 del carriers in our pedigree can change the mRNA splice by reverse-transcriptase PCR and sequencing.

The PRKN mutations vary from point mutations to complex rearrangements, including deletions and/or multiplications of complete exons. Previous studies suggested that a single mutation may cause EOPD or represent a risk factor for late-onset PD.15,18,19 In a few patients, only heterozygous mutations have been detected, suggesting that a second mutation has escaped detection by the methods used or that some mutations in heterozygous forms are sufficient to cause this disorder.20 Our study suggests that the heterozygous T240M or EX 5_6 del mutation is of minor importance in EOPD because 5 heterozygous T240M and 10 heterozygous EX 5_6 del carriers were all exempted from this disorder (the oldest ages of neurologically healthy family members with heterozygous T240M and heterozygous EX 5_6 del were 77 and 75 years, respectively), consistent with loss of function of the PRKN gene. The observation that a 56-year-old compound heterozygous female carrier does not at present manifest any clinical features of PD suggests some interaction of PRKN with other genes (epistasis), that certain environmental effects somehow protect this woman from developing PD, or both.

Correspondence: Joseph Jankovic, MD, Department of Neurology, Baylor College of Medicine, 6550 Fannin St, Suite 1801, Houston, TX 77030 (josephj@bcm.tmc.edu).

Accepted for Publication: September 14, 2005.

Author Contributions: Drs Deng and Le contributed equally to this work. Study concept and design: Deng, Le, Hunter, Ondo, Guo, Xie, and Jankovic. Acquisition of data: Deng, Le, Hunter, Ondo, Guo, Xie, and Jankovic. Analysis and interpretation of data: Deng, Le, Hunter, Guo, Xie, and Jankovic. Drafting of the manuscript: Deng, Le, Hunter, Guo, Xie, and Jankovic. Critical revision of the manuscript for important intellectual content: Deng, Le, Hunter, Ondo, Xie, and Jankovic. Statistical analysis: Deng, Le, Guo, and Xie. Obtained funding: Le. Administrative, technical, and material support: Deng, Le, Hunter, Ondo, Guo, and Xie. Study supervision: Le and Jankovic.

Funding/Support: This study was supported by grants NS 043567 and NS 40370 from the National Institute of Neurological Disorders and Stroke, Bethesda, Md.

Acknowledgment: We thank the participating individuals for their cooperation.

Deng  HLe  WDXie  WJPan  THZhang  XJankovic  J Genetic analysis of parkin co-regulated gene (PACRG) in patients with early-onset parkinsonism. Neurosci Lett 2005;382297- 299
PubMed Link to Article
Polymeropoulos  MHLavedan  CLeroy  E  et al.  Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 1997;2762045- 2047
PubMed Link to Article
Kitada  TAsakawa  SHattori  N  et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392605- 608
PubMed Link to Article
Bonifati  VRizzu  Pvan Baren  MJ  et al.  Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299256- 259
PubMed Link to Article
Valente  EMAbou-Sleiman  PMCaputo  V  et al.  Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004;3041158- 1160
PubMed Link to Article
Di Fonzo  ARohe  CFFerreira  J  et al.  A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 2005;365412- 415
PubMed Link to Article
Deng  HLe  WDGuo  YIHunter  CBXie  WJJankovic  J Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation. Ann Neurol 2005;57933- 934
PubMed Link to Article
Lucking  CBDurr  ABonifati  V  et al. French Parkinson's Disease Genetics Study Group, Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000;3421560- 1567
PubMed Link to Article
Gelb  DJOliver  EGilman  S Diagnostic criteria for Parkinson's disease. Arch Neurol 1999;5633- 39
PubMed Link to Article
Tenan  MBenedetti  SFinocchiaro  G Deletion and transfection analysis of the p15/MTS2 gene in malignant gliomas. Biochem Biophys Res Commun 1995;217195- 202
PubMed Link to Article
Hedrich  KKann  MLanthaler  AJ  et al.  The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism. Hum Mol Genet 2001;101649- 1656
PubMed Link to Article
Livak  KJSchmittgen  TD Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods 2001;25402- 408
PubMed Link to Article
Djarmati  AHedrich  KSvetel  M  et al.  Detection of Parkin (PARK2) and DJ1 (PARK7) mutations in early-onset Parkinson disease: parkin mutation frequency depends on ethnic origin of patients. Hum Mutat 2004;23525
PubMed Link to Article
Pinna  LA Casein kinase 2: an “eminence grise” in cellular regulation? Biochim Biophys Acta 1990;1054267- 284
PubMed Link to Article
Foroud  TUniacke  SKLiu  L  et al.  Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology 2003;60796- 801
PubMed Link to Article
Hattori  NMatsumine  HAsakawa  S  et al.  Point mutations (Thr240Arg and Gln311Stop) in the parkin gene. Biochem Biophys Res Commun 1998;249754- 758
PubMed Link to Article
Jiang  HJiang  QFeng  J Parkin increases dopamine uptake by enhancing the cell surface expression of dopamine transporter. J Biol Chem 2004;27954380- 54386
PubMed Link to Article
Maruyama  MIkeuchi  TSaito  M  et al.  Novel mutations, pseudo-dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism. Ann Neurol 2000;48245- 250
PubMed Link to Article
Poorkaj  PMoses  LMontimurro  JSNutt  JGSchellenberg  GDPayami  H Parkin mutation dosage and the phenomenon of anticipation: a molecular genetic study of familial parkinsonism. BMC Neurol 2005;54
PubMed Link to Article
Bertoli-Avella  AMGiroud-Benitez  JLAkyol  A  et al. Italian Parkinson Genetics Network, Novel parkin mutations detected in patients with early-onset Parkinson's disease. Mov Disord 2005;20424- 431
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Sequencing analysis of the parkin gene (PRKN). A, C>T (NT_007422, nt 754455; T240M) substitution in exon 6 in the PRKN gene (genomic DNA). The arrow shows the nucleotide mutation. B, Abnormal splice (EX 5_6 del) in the PRKN gene (complementary DNA).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The early-onset Parkinson disease (EOPD) pedigree with the compound heterozygous mutations of the parkin gene (PRKN) (T240M and EX 5_6 del). The sex of some family members has been masked for confidentiality reasons. Years indicate present age. D indicates the allele for the EX 5_6 del mutation; M, the allele for the T240M mutation; W, wild-type allele; arrow, the proband; circles, women; filled symbols, individuals manifesting PD; and squares, men.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Clinical Characteristics of Patients With PRKN Mutations

References

Deng  HLe  WDXie  WJPan  THZhang  XJankovic  J Genetic analysis of parkin co-regulated gene (PACRG) in patients with early-onset parkinsonism. Neurosci Lett 2005;382297- 299
PubMed Link to Article
Polymeropoulos  MHLavedan  CLeroy  E  et al.  Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 1997;2762045- 2047
PubMed Link to Article
Kitada  TAsakawa  SHattori  N  et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392605- 608
PubMed Link to Article
Bonifati  VRizzu  Pvan Baren  MJ  et al.  Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299256- 259
PubMed Link to Article
Valente  EMAbou-Sleiman  PMCaputo  V  et al.  Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004;3041158- 1160
PubMed Link to Article
Di Fonzo  ARohe  CFFerreira  J  et al.  A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 2005;365412- 415
PubMed Link to Article
Deng  HLe  WDGuo  YIHunter  CBXie  WJJankovic  J Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation. Ann Neurol 2005;57933- 934
PubMed Link to Article
Lucking  CBDurr  ABonifati  V  et al. French Parkinson's Disease Genetics Study Group, Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000;3421560- 1567
PubMed Link to Article
Gelb  DJOliver  EGilman  S Diagnostic criteria for Parkinson's disease. Arch Neurol 1999;5633- 39
PubMed Link to Article
Tenan  MBenedetti  SFinocchiaro  G Deletion and transfection analysis of the p15/MTS2 gene in malignant gliomas. Biochem Biophys Res Commun 1995;217195- 202
PubMed Link to Article
Hedrich  KKann  MLanthaler  AJ  et al.  The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism. Hum Mol Genet 2001;101649- 1656
PubMed Link to Article
Livak  KJSchmittgen  TD Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods 2001;25402- 408
PubMed Link to Article
Djarmati  AHedrich  KSvetel  M  et al.  Detection of Parkin (PARK2) and DJ1 (PARK7) mutations in early-onset Parkinson disease: parkin mutation frequency depends on ethnic origin of patients. Hum Mutat 2004;23525
PubMed Link to Article
Pinna  LA Casein kinase 2: an “eminence grise” in cellular regulation? Biochim Biophys Acta 1990;1054267- 284
PubMed Link to Article
Foroud  TUniacke  SKLiu  L  et al.  Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology 2003;60796- 801
PubMed Link to Article
Hattori  NMatsumine  HAsakawa  S  et al.  Point mutations (Thr240Arg and Gln311Stop) in the parkin gene. Biochem Biophys Res Commun 1998;249754- 758
PubMed Link to Article
Jiang  HJiang  QFeng  J Parkin increases dopamine uptake by enhancing the cell surface expression of dopamine transporter. J Biol Chem 2004;27954380- 54386
PubMed Link to Article
Maruyama  MIkeuchi  TSaito  M  et al.  Novel mutations, pseudo-dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism. Ann Neurol 2000;48245- 250
PubMed Link to Article
Poorkaj  PMoses  LMontimurro  JSNutt  JGSchellenberg  GDPayami  H Parkin mutation dosage and the phenomenon of anticipation: a molecular genetic study of familial parkinsonism. BMC Neurol 2005;54
PubMed Link to Article
Bertoli-Avella  AMGiroud-Benitez  JLAkyol  A  et al. Italian Parkinson Genetics Network, Novel parkin mutations detected in patients with early-onset Parkinson's disease. Mov Disord 2005;20424- 431
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 13

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles