No Association Between Genetic Polymorphism at Codon 129 of the Prion Protein Gene and Primary Progressive Multiple Sclerosis | Genetics and Genomics | JAMA Neurology | JAMA Network
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Prion Protein Codon 129 Allele Frequencies in Patients With PPMS or RRMS and Controls
Prion Protein Codon 129 Allele Frequencies in Patients With PPMS or RRMS and Controls
Research Letter
February 2011

No Association Between Genetic Polymorphism at Codon 129 of the Prion Protein Gene and Primary Progressive Multiple Sclerosis

Author Affiliations

Author Affiliations: Neurology Section, Veterans Affairs North Texas Health Care System, Medical Service, Dallas (Dr Stüve); Department of Neurology, University of Texas Southwestern Medical Center at Dallas (Drs Stüve and Lambracht-Washington); Department of Neurology, University of California, San Francisco (Dr Wang); Department of Neurology, Ruhr University Bochum, Germany (Dr Chan); Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Germany (Drs Hemmer and Cepok); Department of Neurology, Georg August University Göttingen, Göttingen, Germany (Dr Nessler); Department of Neurology, Johannes Gutenberg University Mainz, Mainz, Germany (Dr Zipp); Department of Neurology, University of Virginia, Charlottesville (Dr Goldman); Department of Neurology, Inflammatory Disorders of the Nervous System and Neurooncology, University of Münster, Münster, Germany (Dr Meuth); Institute for Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany (Dr Korth).

Arch Neurol. 2011;68(2):264-271. doi:10.1001/archneurol.2010.354

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Approximately 10% to 20% of patients with MS are diagnosed with primary progressive MS (PPMS), defined as a disease course with gradual accumulation of disability without any clinical attacks or remission from onset.1 Primary progressive MS is considered by many to have more neurodegenerative characteristics than other MS phenotypes. In addition, and perhaps supportive of the notion that PPMS has a degenerative rather than an inflammatory pathogenesis, are that (1) immune therapies are ineffective, (2) the age at onset is typically around 40 years and thus significantly later than that of relapsing-remitting MS,2-5 and (3) that there appears to be no sex predilection.3

The endogenous cellular prion protein (PrPc) is an α-helical glycophosphatidylinositol-anchored sialoglycoprotein. The PrPc protein is highly expressed in neurons, lymphoid cells, and myeloid cells. A single-nucleotide polymorphism (SNP) at codon 129 of the PrP gene (Prnp), which is located on chromosome 20p12, has been shown to have a significant effect on the clinical course of numerous nonprion neurodegenerative disorders of the central nervous system including Alzheimer disease, Down syndrome, and Wilson disease.6-10 In all of these disorders, methionine/valine heterozygosity is associated with less severe clinical disease. Finally, the Prnp 129 SNP also appears to have a negative effect on long-term memory in adult and senescent healthy individuals.11-13 The mechanisms by which the Prnp SNP 129 alters central nervous system function remain to be elucidated.

Given that PPMS is considered a neurodegenerative disorder, we hypothesized in this study that Prnp SNP 129 has an effect on susceptibility to this distinct MS phenotype.

To determine whether the Prnp 129 M/V SNP plays a role in PPMS susceptibility, we assessed the genotypes of 498 patients with PPMS and 600 healthy controls. Appropriate institutional review boards had approved all studies, and informed consent was obtained from all participants. 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).

The female to male ratio among patients with PPMS was 1:1. No deviations from Hardy-Weinberg equilibrium were observed for genotypes in the patients (Table). There was no statistically significant difference in frequency of Prnp 129 genotypes between patients with PPMS and controls (P = .14) (Table). There was also no difference in allelic frequency distributions between the 498 patients with PPMS and 979 patients with relapsing-remitting MS (P = .23) (Table). No difference in allelic transmission was observed in either subgroup.

While the results of this association analysis do not suggest the role of an SNP in Prnp 129 in PPMS susceptibility, our study was almost certainly underpowered to conclusively eliminate this mutation as a susceptibility factor. Our negative results may also be consistent with recent pathological studies that suggested a strong association between inflammation and neurodegeneration in progressive MS.14 Therefore, in contrast to other typical neurodegenerative disorders, the pathology of progressive MS may be consistent with that of an inflammatory disease rather than degenerative disease in some patients.

We were unable to study the role of Prnp 129 on the disease course of PPMS, as clinical and neuroimaging information was only available on a very small subset of patients. As larger patient databases are being developed, we will be able to study the effect of this SNP on clinical and paraclinical in patients with this disorder.

Correspondence: Dr Stüve, Neurology Section, Veterans Affairs North Texas Health Care System, Medical Service, 4500 S Lancaster Rd, Dallas, TX 75216 (

Financial Disclosure: None reported.

Funding/Support: This study was supported by a Merit Review, Department of Veterans Affairs (Dr Stüve).

Additional Contributions: The authors wish to thank the individuals who participated in this study. In addition, the authors would like to thank Holly Smith for her support, and Jorge Oksenberg, PhD, from the University of California, San Francisco, for his tremendous assistance in designing the study, helping with all technical aspects of the study, and preparing the manuscript. The authors would also like to thank the Accelerated Cure Project for Multiple Sclerosis for making available samples for the project.

This article was corrected on February 14, 2011.

Lublin  FDReingold  SCNational Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis, Defining the clinical course of multiple sclerosis: results of an international survey.  Neurology 1996;46 (4) 907- 911PubMedGoogle ScholarCrossref
Confavreux  CAimard  GDevic  M Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients.  Brain 1980;103 (2) 281- 300PubMedGoogle ScholarCrossref
Weinshenker  BGBass  BRice  GP  et al.  The natural history of multiple sclerosis: a geographically based study I: clinical course and disability.  Brain 1989;112 (pt 1) 133- 146PubMedGoogle ScholarCrossref
Andersson  PBWaubant  EGee  LGoodkin  DE Multiple sclerosis that is progressive from the time of onset: clinical characteristics and progression of disability.  Arch Neurol 1999;56 (9) 1138- 1142PubMedGoogle ScholarCrossref
Bashir  KWhitaker  JN Clinical and laboratory features of primary progressive and secondary progressive MS.  Neurology 1999;53 (4) 765- 771PubMedGoogle ScholarCrossref
Dermaut  BCroes  EARademakers  R  et al.  PRNP Val129 homozygosity increases risk for early-onset Alzheimer's disease.  Ann Neurol 2003;53 (3) 409- 412PubMedGoogle ScholarCrossref
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- 315PubMedGoogle ScholarCrossref
Riemenschneider  MKlopp  NXiang  W  et al.  Prion protein codon 129 polymorphism and risk of Alzheimer disease.  Neurology 2004;63 (2) 364- 366PubMedGoogle ScholarCrossref
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- 692PubMedGoogle ScholarCrossref
Grubenbecher  SStüve  OHefter  HKorth  C Prion protein gene codon 129 modulates clinical course of neurological Wilson disease.  Neuroreport 2006;17 (5) 549- 552PubMedGoogle ScholarCrossref
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- 2246PubMedGoogle ScholarCrossref
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- 737PubMedGoogle ScholarCrossref
Croes  EADermaut  BHouwing-Duistermaat  JJ  et al.  Early cognitive decline is associated with prion protein codon 129 polymorphism.  Ann Neurol 2003;54 (2) 275- 276PubMedGoogle ScholarCrossref
Frischer  JMBramow  SDal-Bianco  A  et al.  The relation between inflammation and neurodegeneration in multiple sclerosis brains.  Brain 2009;132 (pt 5) 1175- 1189PubMedGoogle ScholarCrossref