Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of cytosine-adenine-guanine (CAG) repeats in the Huntingtin gene Htt. To facilitate research into HD, we have derived 4 human embryonic stem cell (hESC) lines containing ≥40CAG repeats in exon 1 of Htt: SIVF017-HD (CAG40), SIVF018-HD (CAG46), SIVF020-HD (CAG48), and SIVF046-HD (CAG45). Additionally, we have derived a normal sibling-matched control for SIVF020-HD, cell line SIVF019. All 5 hESC lines had a normal karyotype, expressed pluripotency markers including Oct4, SSEA3, and Tra-1-81, and could be maintained in culture for multiple (>40) passages. Teratoma studies revealed that the hESC lines were capable of differentiating into cells representative of the 3 germ layers. Furthermore, in vitro neuronal differentiation experiments have confirmed that the hESC lines were able to generate MAP2-positive neuronal cells that express the Htt protein. Combined, these experiments confirm that the cell lines represent pluripotent stem cell lines. These HD-affected hESC lines will be made available to biomedical research laboratories and will provide a valuable tool to investigate the mechanisms and potential treatments for HD.
The Huntington's Disease Collaborative Research Group. 1993. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell, 72:971–983.
3.
QuarrellOW, RigbyAS, BarronL, CrowY, DaltonA, DennisN, FryerAE, HeydonF, KinningE, LashwoodA, LosekootM, MargerisonL, McDonnellS, MorrisonPJ, NormanA, PetersonM, RaymondFL, SimpsonS, ThompsonE, WarnerJ. 2007. Reduced penetrance alleles for Huntington's disease: a multi-centre direct observational study. J Med Genet, 44:e68.
4.
TeleniusH, KremerHP, TheilmannJ, AndrewSE, AlmqvistE, AnvretM, GreenbergC, GreenbergJ, LucotteG, SquitieriF. 1993. Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum Mol Genet, 2:1535–1540.
5.
KremerB, AlmqvistE, TheilmannJ, SpenceN, TeleniusH, GoldbergYP, HaydenMR. 1995. Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes. Am J Hum Genet, 57:343–350.
6.
ShelbournePF, Keller-McGandyC, BiWL, YoonSR, DubeauL, VeitchNJ, VonsattelJP, WexlerNS, ArnheimN, AugoodSJ. 2007. Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. Hum Mol Genet, 16:1133–1142.
7.
KennedyL, EvansE, ChenCM, CravenL, DetloffPJ, EnnisM, ShelbournePF. 2003. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet, 12:3359–3367.
NasirJ, FlorescoSB, O'KuskyJR, DiewertVM, RichmanJM, ZeislerJ, BorowskiA, MarthJD, PhillipsAG, HaydenMR. 1995. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell, 81:811–823.
10.
DragatsisI, LevineMS, ZeitlinS. 2000. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet, 26:300–306.
Gerecht-NirS, Itskovitz-EldorJ. 2004. Human embryonic stem cells: a potential source for cellular therapy. Am J Transplant, 4,Suppl 6:51–57.
15.
ChapinRE, StedmanDB. 2009. Endless possibilities: stem cells and the vision for toxicology testing in the 21st century. Toxicol Sci, 112:17–22.
16.
PoutonCW, HaynesJM. 2007. Embryonic stem cells as a source of models for drug discovery. Nat Rev Drug Discov, 6:605–616.
17.
CrookJM, KobayashiNR. 2008. Human stem cells for modeling neurological disorders: accelerating the drug discovery pipeline. J Cell Biochem, 105:1361–1366.
18.
AubryL, BugiA, LefortN, RousseauF, PeschanskiM, PerrierAL. 2008. Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc Natl Acad Sci USA, 105:16707–16712.
19.
HenmanM, CattJW, WoodT, BowmanMC, de BoerKA, JansenRP. 2005. Elective transfer of single fresh blastocysts and later transfer of cryostored blastocysts reduces the twin pregnancy rate and can improve the in vitro fertilization live birth rate in younger women. Fertil Steril, 84:1620–1627.
20.
McArthurSJ, LeighD, MarshallJT, GeeAJ, de BoerKA, JansenRP. 2008. Blastocyst trophectoderm biopsy and preimplantation genetic diagnosis for familial monogenic disorders and chromosomal translocations. Prenat Diagn, 28:434–442.
21.
PeuraT, BosmanA, ChamiO, JansenRP, TexlovaK, StojanovT. 2008. Karyotypically normal and abnormal human embryonic stem cell lines derived from PGD-analyzed embryos. Cloning Stem Cells, 10:203–216.
22.
PeuraTT, SchaftJ, StojanovT. 2010. Derivation of human embryonic stem cell lines from vitrified human embryos. Methods Mol Biol, 584:21–54.
23.
PaschenW, BlackstoneCD, HuganirRL, RossCA. 1994. Human GluR6 kainate receptor (GRIK2): molecular cloning, expression, polymorphism, and chromosomal assignment. Genomics, 20:435–440.
24.
AndrewSE, GoldbergYP, TheilmannJ, ZeislerJ, HaydenMR. 1994. A CCG repeat polymorphism adjacent to the CAG repeat in the Huntington disease gene: implications for diagnostic accuracy and predictive testing. Hum Mol Genet, 3:65–67.
Huntington Study Group. 2001. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology, 57:397–404.
29.
Huntington Study Group. 2003. Dosage effects of riluzole in Huntington's disease: a multicenter placebo-controlled study. Neurology, 61:1551–1556.
30.
MillerM. 2009. Minocycline Phase II Clinical Trials Results are DisappointingHD Lighthouse. 23-4-2009. Ref Type: Internet Communicationhttp://hdlighthouse.org/showUpdate.php?p_articleNumber=628
31.
FeckeW, GianfriddoM, GaviraghiG, TerstappenGC, HeitzF. 2009. Small molecule drug discovery for Huntington's Disease. Drug Discov Today, 14:453–464.
32.
BrinkmanRR, MezeiMM, TheilmannJ, AlmqvistE, HaydenMR. 1997. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet, 60:1202–1210.
33.
AndrewSE, GoldbergYP, KremerB, TeleniusH, TheilmannJ, AdamS, StarrE, SquitieriF, LinB, KalchmanMA. 1993. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet, 4:398–403.
34.
RubinszteinDC, LeggoJ, ChianoM, DodgeA, NorburyG, RosserE, CraufurdD. 1997. Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc Natl Acad Sci USA, 94:3872–3876.
35.
AzizNA, JurgensCK, LandwehrmeyerGB, van Roon-MomWM, van OmmenGJ, StijnenT, RoosRA. 2009. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. Neurology, 73:1280–1285.
36.
NazeP, VuillaumeI, DesteeA, PasquierF, SablonniereB. 2002. Mutation analysis and association studies of the ubiquitin carboxy-terminal hydrolase L1 gene in Huntington's disease. Neurosci Lett, 328:1–4.
37.
VerlinskyY, StrelchenkoN, KukharenkoV, RechitskyS, VerlinskyO, GalatV, KulievA. 2005. Human embryonic stem cell lines with genetic disorders. Reprod Biomed Online, 10:105–110.
38.
NiclisJC, TrounsonAO, DottoriM, EllisdonAM, BottomleySP, VerlinskyY, CramDS. 2009. Human embryonic stem cell models of Huntington disease. Reprod Biomed Online, 19:106–113.
39.
MateizelI, DeTN, UllmannU, CauffmanG, SermonK, Van de VeldeH, De RyckeM, DegreefE, DevroeyP, LiebaersI, VanSA. 2006. Derivation of human embryonic stem cell lines from embryos obtained after IVF and after PGD for monogenic disorders. Hum Reprod, 21:503–511.
40.
WadmanM. 2010. Diseased cells fail to win approval. Nature, 465:852.
LiuSV. 2008. iPS cells: a more critical review. Stem Cells Dev, 17:391–397.
43.
FengQ, LuSJ, KlimanskayaI, GomesI, KimD, ChungY, HonigGR, KimKS, LanzaR. 2010. Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. Stem Cells, 28:704–712.
44.
HuBY, WeickJP, YuJ, MaLX, ZhangXQ, ThomsonJA, ZhangSC. 2010. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci USA, 107:4335–4340.
45.
OsafuneK, CaronL, BorowiakM, MartinezRJ, Fitz-GeraldCS, SatoY, CowanCA, ChienKR, MeltonDA. 2008. Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol, 26:313–315.
46.
CurtisMA, PenneyEB, PearsonAG, van Roon-MomWM, ButterworthNJ, DragunowM, ConnorB, FaullRL. 2003. Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain. Proc Natl Acad Sci USA, 100:9023–9027.
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