인간프리온단백질 유전자의 다형성에 관한 키타모토 박사팀의 연구결과입니다. 논문의 요지는 마우스를 사용한 동물실험 결과, 프리온 질병이 코돈 129 MM형에서 잘 걸리고 M과 V가 섞여있는 MV형은 잘 안걸리는 것처럼, 코돈 219에서도 EE형이나 KK형은 잘 걸리는데 EK형은 잘 안걸리는 것으로 나타났다는 내용입니다.
* 참고 : 코돈 219 Glu(E)/Lys(K)
219 다형성은 코카서스 인종에게는 나타나지 않았고… 일본인의 경우 E/E 86%, E/K(=Glu/Lys) 14%, K/K 0% … 한국인의 경우 E/E 92.06%, E/K(=Glu/Lys) 7.94%, K/K 0% .. 중국인의 경우… 한(漢)족 E/E 89.8%, E/K(=Glu/Lys) 10.2%, K/K 0%… 회(回)족 E/E 95.5%, E/K(=Glu/Lys) 4.5%, K/K 0%… 위그르족 E/E 97.8%, E/K(=Glu/Lys) 2.2%, K/K 0%로 나타났습니다.
그러나 219 다형성의 차이가 vCJD의 저항성의 차이로 해석될 수 있을 것인가에 대해서는 아직 결론을 내리기 힘들 것 같습니다.
학계에서는 117번 코돈의 유전자 다형성에 대해서도 관심을 가지고 있는데… A117A가 영국인에서는 11%, 독일인에서는 5.4%, 터기인에서는 5%, 위그르인에서는 1.3%가 나타난데 비해 한족, 회족, 일본인, 타이인에게서는 이러한 돌연변이가 나타나지 않았다고 보고되어 있습니다. (Geng-Fu Xiao et al, ‘Polymorphisms of the PRNP gene in Chinese populations and the identification of a novel insertion mutation’, European Journal of Human Genetics (2004) 12, 867–870)
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Human Prion Protein (PrP) 219K Is Converted to PrPSc but Shows Heterozygous Inhibition in Variant Creutzfeldt-Jakob Disease Infection*
Masaki Hizume‡§1,
Atsushi Kobayashi‡1,
Kenta Teruya¶,
Hiroaki Ohashi∥,
James W. Ironside**,
Shirou Mohri‡‡ and
Tetsuyuki Kitamoto‡2
+ Author Affiliations
‡Division of CJD Science and Technology, ¶Division of Prion Biology, Department of Prion Research, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan, the ∥Central Institute for Experimental Animals, Kawasaki 216-0011, Japan, the **National CJD Surveillance Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom, the ‡‡Prion Disease Research Center, National Institute of Animal Health, Tsukuba 305-0856, Japan, and the §Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
2 To whom correspondence should be addressed: Division of CJD Science and Technology, Dept. of Prion Research, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai 980-8575, Japan. Tel.: 81-22-717-8143; Fax: 81-22-717-8148; E-mail: kitamoto@mail.tains.tohoku.ac.jp.
출처 : http://www.jbc.org/content/284/6/3603.abstract
Abstract
Prion protein gene (PRNP) E219K is a human polymorphism commonly occurring in Asian populations but is rarely found in patients with sporadic Creutzfeldt-Jakob disease (CJD). Thus the polymorphism E219K has been considered protective against sporadic CJD. The corresponding mouse prion protein (PrP) polymorphism variant (mouse PrP 218K) is not converted to the abnormal isoform (PrPSc) and shows a dominant negative effect on wild-type PrP conversion. To define the conversion activity of this human molecule, we herein established knock-in mice with human PrP 219K and performed a series of transmission experiments with human prions. Surprisingly, the human PrP 219K molecule was converted to PrPSc in variant CJD infection, and the conversion occurred more efficiently than PrP 219E molecule. Notably the knock-in mice with PRNP codon 219E/K showed the least efficient conversion compared with their hemizygotes with PRNP codon 219E/0 or codon 219K/0, or homozygotes with PRNP codon 219E/E or codon 219K/K. This phenomenon indicated heterozygous inhibition. This heterozygous inhibition was observed also in knock-in mice with PRNP codon 129M/V genotype. In addition to variant CJD infection, the human PrP 219K molecule is conversion-competent in transmission experiments with sporadic CJD prions. Therefore, the protective effect of PRNP E219K against sporadic CJD might be due to heterozygous inhibition.
Footnotes
↵3 The abbreviations used are: CJD, Creutzfeldt-Jakob disease; vCJD, variant CJD; sCJD, sporadic CJD; PrP, prion protein; PrPC, normal cellular isoform of PrP; PrPSc, abnormal isoform of PrP; FDC, follicular dendritic cell; PRNP, human prion protein gene; prnp, murine prion protein gene.
↵* This work was supported by the Promotion of Fundamental Studies in Health Science of National Institute of Biomedical Innovation (to H. O., S. M., and T. K.), a grant from the Ministry of Health, Labor, and Welfare (to A. K., S. M., and T. K.), and a Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (to A. K. and T. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵ The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.
↵1 Both authors contributed equally to this work.
Received December 9, 2008.
The American Society for Biochemistry and Molecular Biology, Inc.
