Quantifying prion disease penetrance using large population control cohorts

被引：258

作者：

Minikel, Eric Vallabh ^{[1
,2
,3
,4
]}

Vallabh, Sonia M. ^{[1
,3
,4
]}

Lek, Monkol ^{[1
,2
]}

Estrada, Karol ^{[1
,2
]}

Samocha, Kaitlin E. ^{[1
,2
,3
]}

Sathirapongsasuti, J. Fah ^{[5
]}

McLean, Cory Y. ^{[5
]}

Tung, Joyce Y. ^{[5
]}

Yu, Linda P. C. ^{[5
]}

Gambetti, Pierluigi ^{[6
]}

Blevins, Janis ^{[6
]}

Zhang, Shulin ^{[7
]}

Cohen, Yvonne ^{[6
]}

Chen, Wei ^{[6
]}

Yamada, Masahito ^{[8
]}

Hamaguchi, Tsuyoshi ^{[8
]}

Sanjo, Nobuo ^{[9
]}

Mizusawa, Hidehiro ^{[10
]}

Nakamura, Yosikazu ^{[11
]}

Kitamoto, Tetsuyuki ^{[12
]}

Collins, Steven J. ^{[13
]}

Boyd, Alison ^{[13
]}

Will, Robert G. ^{[14
]}

Knight, Richard ^{[14
]}

Ponto, Claudia ^{[15
]}

Zerr, Inga ^{[15
]}

Kraus, Theo F. J. ^{[16
]}

Eigenbrod, Sabina ^{[16
]}

Giese, Armin ^{[16
]}

Calero, Miguel ^{[17
]}

de Pedro-Cuesta, Jesus ^{[17
]}

HaiK, Stephane ^{[18
,19
,20
]}

Laplanche, Jean-Louis ^{[21
]}

Bouaziz-Amar, Elodie ^{[21
]}

Brandel, Jean-Philippe ^{[18
,19
,20
]}

Capellari, Sabina ^{[22
,23
]}

Parchi, Piero ^{[22
,23
]}

Poleggi, Anna ^{[24
]}

Ladogana, Anna ^{[24
]}

O'Donnell-Luria, Anne H. ^{[1
,2
,25
]}

Karczewski, Konrad J. ^{[1
,2
]}

Marshall, Jamie L. ^{[1
,2
]}

Boehnke, Michael ^{[26
,27
]}

Laakso, Markku ^{[28
,29
]}

Mohlke, Karen L. ^{[30
]}

Kahler, Anna ^{[31
]}

Chambert, Kimberly

McCarroll, Steven ^{[32
]}

Sullivan, Patrick F. ^{[30
,31
]}

Hultman, Christina M. ^{[31
]}

机构：

[1] Broad Inst Massachusetts Inst Technol MIT & Harva, Program Med & Populat Genet, Cambridge, MA 02142 USA

[2] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[3] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA 02115 USA

[4] Prion Alliance, Cambridge, MA 02139 USA

[5] 23&Me Inc, Res, Mountain View, CA 94041 USA

[6] Natl Pr Dis Pathol Surveillance Ctr, Cleveland, OH 44106 USA

[7] Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA

[8] Kanazawa Univ, Grad Sch Med Sci, Dept Neurol & Neurobiol Aging, Kanazawa, Ishikawa 9208640, Japan

[9] Tokyo Med & Dent Univ, Grad Sch, Dept Neurol & Neurol Sci, Tokyo 1138519, Japan

[10] Natl Ctr Neurol & Psychiat, Natl Ctr Hosp, Tokyo 1878551, Japan

[11] Jichi Med Univ, Dept Publ Hlth, Shimotsuke 3290498, Japan

[12] Tohoku Univ, Grad Sch Med, Dept Neurol Sci, Sendai, Miyagi 9808575, Japan

[13] Univ Melbourne, Australian Natl Creutzfeldt Jakob Dis Registry, Parkville, Vic 3010, Australia

[14] Western Gen Hosp, Natl Creutzfeldt Jakob Dis Res & Surveillance Uni, Edinburgh EH4 2XU, Midlothian, Scotland

[15] Univ Gottingen, Natl Reference Ctr Surveillance Human Transmissib, D-37073 Gottingen, Germany

[16] Univ Munich, Ctr Neuropathol & Pr Res ZNP, Marchioninistr 15, D-81377 Munich, Germany

[17] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain

[18] Sorbonne Univ, CNRS UMR 7225, INSERM U1127, F-75013 Paris, France

[19] Univ Paris 06, UMR S 1127, Inst Cerveau & Moelle Epiniere, F-75013 Paris, France

[20] Grp Hosp Pitie Salpetriere, AP HP, Cellule Natl Reference Malad Creutzfeldt Jakob, F-75013 Paris, France

[21] Hop Lariboisiere, AP HP, Serv Biochim & Biol Mol, F-75010 Paris, France

[22] Inst Neurol Sci, IRCCS, I-40123 Bologna, Italy

[23] Univ Bologna, Dept Biomed & Neuromotor Sci, I-40126 Bologna, Italy

[24] Ist Super Sanita, Dept Cell Biol & Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy

[25] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[26] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA

[27] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[28] Univ Eastern Finland, Dept Med, Kuopio 70210, Finland

[29] Kuopio Univ Hosp, SF-70210 Kuopio, Finland

[30] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA

[31] Karolinska Inst, SE-17177 Stockholm, Sweden

[32] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[33] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[34] Erasmus Med Ctr MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands

[35] Univ Med Ctr, Dept Pathol, Dutch Surveillance Ctr Pr Dis, NL-3584 CX Utrecht, Netherlands

[36] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2016年 / 8卷 / 322期

基金：

英国医学研究理事会; 美国国家科学基金会;

关键词：

CREUTZFELDT-JAKOB-DISEASE; STRAUSSLER-SCHEINKER-DISEASE; FATAL FAMILIAL INSOMNIA; PROTEIN GENE MUTATION; UNCOMMON POLYMORPHISM RATHER; AMYLOID PRECURSOR GENE; PRNP GENE; R208H MUTATION; INSERTIONAL MUTATION; REPEAT INSERTION;

D O I：

10.1126/scitranslmed.aad5169

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from < 0.1 to similar to 100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

引用

页数：12

共 180 条

[1] The prion's elusive reason for being [J].

Aguzzi, Adriano ;

Baumann, Frank ;

Bremer, Jullane .

ANNUAL REVIEW OF NEUROSCIENCE, 2008, 31 :439-477

[2] Convection-Enhanced Delivery of AAV2-PrPshRNA in Prion-Infected Mice [J].

Ahn, Misol ;

Bajsarowicz, Krystyna ;

Oehler, Abby ;

Lemus, Azucena ;

Bankiewicz, Krystof ;

DeArmond, Stephen J. .

PLOS ONE, 2014, 9 (05)

[3] A Novel PRNP Y218N Mutation in Gerstmann-Straussler-Scheinker Disease With Neurofibrillary Degeneration [J].

Alzualde, Ainhoa ;

Indakoetxea, Begona ;

Ferrer, Isidre ;

Moreno, Fermin ;

Barandiaran, Myriam ;

Gorostidi, Ana ;

Estanga, Ainara ;

Ruiz, Irune ;

Calero, Miguel ;

van Leeuwen, Fred W. ;

Atares, Begona ;

Juste, Ramon ;

Belen Rodriguez-Martinez, Ana ;

Lopez de Munain, Adolfo .

JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 2010, 69 (08) :789-800

[4] A New Face and New Challenges for Online Mendelian Inheritance in Man (OMIM®) [J].

Amberger, Joanna ;

Bocchini, Carol ;

Hamosh, Ada .

HUMAN MUTATION, 2011, 32 (05) :564-567

[5]

[Anonymous], 1998, DIAGNOSIS AND THERAP

[6] Familial Creutzfeldt-Jakob disease with an R208H-129V haplotype and Kuru plaques [J].

Basset-Leobon, C ;

Uro-Coste, E ;

Peoc'h, K ;

Haik, S ;

Sazdovitch, V ;

Rigal, M ;

Andreoletti, O ;

Hauw, JJ ;

Delisle, MB .

ARCHIVES OF NEUROLOGY, 2006, 63 (03) :449-452

[7] Two-octapeptide repeat deletion of prion protein associated with rapidly progressive dementia [J].

Beck, JA ;

Mead, S ;

Campbell, TA ;

Dickinson, A ;

Wientjens, DPMW ;

Croes, EA ;

Van Duijn, CM ;

Collinge, J .

NEUROLOGY, 2001, 57 (02) :354-356

[8] Prion protein gene M232R variation is probably an uncommon polymorphism rather than a pathogenic mutation [J].

Beck, Jon ;

Collinge, John ;

Mead, Simon .

BRAIN, 2012, 135

[9] PRNP Allelic Series From 19 Years of Prion Protein Gene Sequencing at the MRC Prion Unit [J].

Beck, Jon A. ;

Poulter, Mark ;

Campbell, Tracy A. ;

Adamson, Gary ;

Uphill, James B. ;

Guerreiro, Rita ;

Jackson, Graham S. ;

Stevens, James C. ;

Manji, Hadi ;

Collinge, John ;

Mead, Simon .

HUMAN MUTATION, 2010, 31 (07) :E1551-E1563

[10]

Begg CB, 2002, J NATL CANCER I, V94, P1221

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