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Research Letters |

Genetic Polymorphism at Codon 129 of the Prion Protein Gene Is Not Associated With Multiple Sclerosis FREE

Olaf Stüve, MD, PhD; Carsten Korth, MD, PhD; Pablo Gabatto, BSc; Elizabeth M. Cameron, BSc; Wei Hu, MD, PhD; Todd N. Eagar, PhD; Nancy L. Monson, PhD; Elliot M. Frohman, MD, PhD; Michael K. Racke, MD; Cyrus P. Zabetian, MD, MS; Jorge R. Oksenberg, PhD
Arch Neurol. 2009;66(2):280-281. doi:10.1001/archneur.66.2.280.
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The endogenous cellular prion protein (PrPC) is an α-helical glycophosphatidylinositol-anchored sialoglycoprotein highly expressed in neurons, lymphoid cells, and myeloid cells. In humans, the PrP gene (Prnp) is located on chromosome 20p12. Single-nucleotide polymorphisms (SNPs) in Prnp have been shown to determine the susceptibility to inherited, sporadic, and infectious forms of prion diseases.1 Interestingly, it was also recently shown that the same Prnp129 SNP has a significant effect on the clinical course of numerous nonprion neurodegenerative disorders of the central nervous system (CNS), including early-onset Alzheimer disease,24 Down syndrome,5 and Wilson disease.6 In these studies, methionine/valine (M/V) heterozygosity was associated with less severe clinical disease. Finally, the Prnp129 SNP was also shown to negatively affect long-term memory in adult and senescent healthy individuals.79 The exact mechanisms by which genetic polymorphisms of Prnp alter CNS function and disease phenotypes are largely unknown.

In this study, we investigated the effect of the Prnp129 M/V SNP on disease susceptibility to multiple sclerosis (MS), a human inflammatory neurodegenerative disease of the CNS. To determine whether the Prnp129 M/V SNP plays a role in MS susceptibility, we genotyped 973 families with nuclear MS (n = 2998 individuals). Appropriate institutional review boards approved the studies and informed consent was obtained from all participants. The ratio of women to men for affected individuals was 2.9:1, and 91.7% presented with relapsing-remitting (67.6%) or secondary progressive (24.1%) MS at the time of study entry. Genotypes were generated by a TaqMan allelic discrimination assay on an ABI7900HT genotyping platform using the Assay-by-Design service from Applied Biosystems (Foster City, California). All family genotypes were examined for mendelian inconsistencies using PedCheck (University of Pittsburgh, Pennsylvania),10 and any discrepancies were addressed. No deviations from Hardy-Weinberg equilibrium were observed for genotypes in the patient, parent, or combined group (data not shown).

Family-based association analysis was performed using the reconstructed-combined transmission disequilibrium test11 as implemented in SAS Genetics (v.9.1.3; SAS Institute, Cary, North Carolina). There was no evidence of transmission distortion in this data set (P = .5). Families were stratified by sex and by the presence of HLA-DRB1*1501 in the affected individuals to identify potential genetic interactions. No difference in allelic transmission was observed in either subgroup. The cases from the 973 families with nuclear MS were combined with 490 additional MS cases (total ratio of women to men, 2.7:1) ascertained using identical inclusion criteria and compared with 1131 controls (ratio of women to men, 1.9:1). There was no statistically significant difference in the frequency of Prnp129 genotypes between patients and controls. Allele frequency distributions were similar in patients with mild (EDSS < 3, 15 years after onset) or severe (EDSS > 6 within 10 years after onset) MS (data not shown)12 or when using the Multiple Sclerosis Severity Score13 as a dependent variable (data not shown). Similarly, no effect of Prpn129 on age of onset was detected.

Using the family-based association analysis, we can conclude that an SNP in Prnp129 plays no major role in MS susceptibility. The role of other unlinked polymorphisms or the potential role of Prnp129 in the progression of neuroradiologic or cognitive endpoints of MS cannot be excluded.

ARTICLE INFORMATION

Correspondence: Dr Stüve, Neurology Section, Veterans Affairs North Texas Health Care System, Medical Service, 4500 S Lancaster Rd, Dallas, TX 75216 (olaf.stuve@utsouthwestern.edu).

Author Contributions:Study concept and design: Stüve, Korth, Hu, Frohman, and Oksenberg. Acquisition of data: Stüve, Gabatto, Cameron, Monson, Frohman, Zabetian, and Oksenberg. Analysis and interpretation of data: Stüve, Korth, Eagar, Monson, Frohman, Racke, and Oksenberg. Drafting of the manuscript: Stüve, Korth, Hu, Eagar, Monson, Frohman, and Oksenberg. Critical revision of the manuscript for important intellectual content: Stüve, Korth, Gabatto, Cameron, Frohman, Racke, Zabetian, and Oksenberg. Statistical analysis: Stüve and Oksenberg. Obtained funding: Monson, Racke, Zabetian, and Oksenberg. Administrative, technical, and material support: Stüve, Korth, Gabatto, Hu, Eagar, Frohman, and Zabetian. Study supervision: Stüve, Korth, Monson, Zabetian, and Oksenberg.

Financial Disclosure: None reported.

Additional Contributions: The authors wish to thank the individuals who participated in this study.

Palmer  MSDryden  AJHughes  JTCollinge  J Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 1991;352 (6333) 340- 342
PubMed
Dermaut  BCroes  EARademakers  R  et al.  PRNP Val129 homozygosity increases risk for early-onset Alzheimer's disease. Ann Neurol 2003;53 (3) 409- 412
PubMed
Golanska  EHulas-Bigoszewska  KRutkiewicz  E  et al.  Polymorphisms within the prion (PrP) and prion-like protein (Doppel) genes in AD. Neurology 2004;62 (2) 313- 315
PubMed
Riemenschneider  MKlopp  NXiang  W  et al.  Prion protein codon 129 polymorphism and risk of Alzheimer disease. Neurology 2004;63 (2) 364- 366
PubMed
Del Bo  RComi  GPGiorda  R  et al.  The 129 codon polymorphism of the prion protein gene influences earlier cognitive performance in Down syndrome subjects. J Neurol 2003;250 (6) 688- 692
PubMed
Grubenbecher  SStuve  OHefter  HKorth  C Prion protein gene codon 129 modulates clinical course of neurological Wilson disease. Neuroreport 2006;17 (5) 549- 552
PubMed
Papassotiropoulos  AWollmer  MAAguzzi  AHock  CNitsch  RMde Quervain  DJ The prion gene is associated with human long-term memory. Hum Mol Genet 2005;14 (15) 2241- 2246
PubMed
Berr  CRichard  FDufouil  CAmant  CAlperovitch  AAmouyel  P Polymorphism of the prion protein is associated with cognitive impairment in the elderly: the EVA study. Neurology 1998;51 (3) 734- 737
PubMed
Croes  EADermaut  BHouwing-Duistermaat  JJ  et al.  Early cognitive decline is associated with prion protein codon 129 polymorphism. Ann Neurol 2003;54 (2) 275- 276
PubMed
O'Connell  JRWeeks  DE PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998;63 (1) 259- 266
PubMed
Spielman  RS McGinnis  REEwens  WJ Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993;52 (3) 506- 516
PubMed
Barcellos  LFOksenberg  JRGreen  AJ  et al.  Genetic basis for clinical expression in multiple sclerosis. Brain 2002;125 (pt 1) 150- 158
PubMed
Roxburgh  RHSeaman  SRMasterman  T  et al.  Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology 2005;64 (7) 1144- 1151
PubMed

Figures

Tables

References

Palmer  MSDryden  AJHughes  JTCollinge  J Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 1991;352 (6333) 340- 342
PubMed
Dermaut  BCroes  EARademakers  R  et al.  PRNP Val129 homozygosity increases risk for early-onset Alzheimer's disease. Ann Neurol 2003;53 (3) 409- 412
PubMed
Golanska  EHulas-Bigoszewska  KRutkiewicz  E  et al.  Polymorphisms within the prion (PrP) and prion-like protein (Doppel) genes in AD. Neurology 2004;62 (2) 313- 315
PubMed
Riemenschneider  MKlopp  NXiang  W  et al.  Prion protein codon 129 polymorphism and risk of Alzheimer disease. Neurology 2004;63 (2) 364- 366
PubMed
Del Bo  RComi  GPGiorda  R  et al.  The 129 codon polymorphism of the prion protein gene influences earlier cognitive performance in Down syndrome subjects. J Neurol 2003;250 (6) 688- 692
PubMed
Grubenbecher  SStuve  OHefter  HKorth  C Prion protein gene codon 129 modulates clinical course of neurological Wilson disease. Neuroreport 2006;17 (5) 549- 552
PubMed
Papassotiropoulos  AWollmer  MAAguzzi  AHock  CNitsch  RMde Quervain  DJ The prion gene is associated with human long-term memory. Hum Mol Genet 2005;14 (15) 2241- 2246
PubMed
Berr  CRichard  FDufouil  CAmant  CAlperovitch  AAmouyel  P Polymorphism of the prion protein is associated with cognitive impairment in the elderly: the EVA study. Neurology 1998;51 (3) 734- 737
PubMed
Croes  EADermaut  BHouwing-Duistermaat  JJ  et al.  Early cognitive decline is associated with prion protein codon 129 polymorphism. Ann Neurol 2003;54 (2) 275- 276
PubMed
O'Connell  JRWeeks  DE PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998;63 (1) 259- 266
PubMed
Spielman  RS McGinnis  REEwens  WJ Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993;52 (3) 506- 516
PubMed
Barcellos  LFOksenberg  JRGreen  AJ  et al.  Genetic basis for clinical expression in multiple sclerosis. Brain 2002;125 (pt 1) 150- 158
PubMed
Roxburgh  RHSeaman  SRMasterman  T  et al.  Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology 2005;64 (7) 1144- 1151
PubMed

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