Mapping of the Disease Locus and Identification of As a Candidate Gene in a Canine Model of Primary Open Angle Glaucoma

English version České info

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide, with elevated intraocular pressure as an important risk factor. Increased resistance to outflow of aqueous humor through the trabecular meshwork causes elevated intraocular pressure, but the specific mechanisms are unknown. In this study, we used genome-wide SNP arrays to map the disease gene in a colony of Beagle dogs with inherited POAG to within a single 4 Mb locus on canine chromosome 20. The Beagle POAG locus is syntenic to a previously mapped human quantitative trait locus for intraocular pressure on human chromosome 19. Sequence capture and next-generation sequencing of the entire canine POAG locus revealed a total of 2,692 SNPs segregating with disease. Of the disease-segregating SNPs, 54 were within exons, 8 of which result in amino acid substitutions. The strongest candidate variant causes a glycine to arginine substitution in a highly conserved region of the metalloproteinase ADAMTS10. Western blotting revealed ADAMTS10 protein is preferentially expressed in the trabecular meshwork, supporting an effect of the variant specific to aqueous humor outflow. The Gly661Arg variant in ADAMTS10 found in the POAG Beagles suggests that altered processing of extracellular matrix and/or defects in microfibril structure or function may be involved in raising intraocular pressure, offering specific biochemical targets for future research and treatment strategies.

Vyšlo v časopise: Mapping of the Disease Locus and Identification of As a Candidate Gene in a Canine Model of Primary Open Angle Glaucoma. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1001306
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001306

Souhrn

Zdroje

1. KwonYH

FingertJH

KuehnMH

AlwardWL

2009 Primary open-angle glaucoma. N Engl J Med 360 1113 1124

2. JohnsonM

2006 ‘What controls aqueous humour outflow resistance?’. Exp Eye Res 82 545 557

3. AcottTS

KelleyMJ

2008 Extracellular matrix in the trabecular meshwork. Exp Eye Res 86 543 561

4. AllinghamRR

LiuY

RheeDJ

2009 The genetics of primary open-angle glaucoma: a review. Exp Eye Res 88 837 844

5. GelattKN

PeifferRLJr

GwinRM

GumGG

WilliamsLW

1977 Clinical manifestations of inherited glaucoma in the beagle. Invest Ophthalmol Vis Sci 16 1135 1142

6. PeifferRLJr

GumGG

GrimsonRC

GelattKN

1980 Aqueous humor outflow in beagles with inherited glaucoma: constant pressure perfusion. Am J Vet Res 41 1808 1813

7. BrooksDE

StrubbeDT

KubilisPS

MacKayEO

SamuelsonDA

1995 Histomorphometry of the optic nerves of normal dogs and dogs with hereditary glaucoma. Exp Eye Res 60 71 89

8. GelattKN

GumGG

1981 Inheritance of primary glaucoma in the beagle. Am J Vet Res 42 1691 1693

9. Lindblad-TohK

WadeCM

MikkelsenTS

KarlssonEK

JaffeDB

2005 Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438 803 819

10. KarlssonEK

BaranowskaI

WadeCM

Salmon HillbertzNH

ZodyMC

2007 Efficient mapping of mendelian traits in dogs through genome-wide association. Nat Genet 39 1321 1328

11. ParkerHG

VonHoldtBM

QuignonP

MarguliesEH

ShaoS

2009 An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science 325 995 998

12. DrogemullerC

KarlssonEK

HytonenMK

PerloskiM

DolfG

2008 A mutation in hairless dogs implicates FOXI3 in ectodermal development. Science 321 1462

13. DuggalP

KleinAP

LeeKE

KleinR

KleinBE

2007 Identification of novel genetic loci for intraocular pressure: a genomewide scan of the Beaver Dam Eye Study. Arch Ophthalmol 125 74 79

14. PorterS

ClarkIM

KevorkianL

EdwardsDR

2005 The ADAMTS metalloproteinases. Biochem J 386 15 27

15. SomervilleRP

JungersKA

ApteSS

2004 Discovery and characterization of a novel, widely expressed metalloprotease, ADAMTS10, and its proteolytic activation. J Biol Chem 279 51208 51217

16. ApteSS

2009 A disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif (ADAMTS) superfamily: functions and mechanisms. J Biol Chem 284 31493 31497

17. KumarP

HenikoffS

NgPC

2009 Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4 1073 1081

18. YueP

MelamudE

MoultJ

2006 SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinformatics 7 166

19. SmithKM

GaultierA

CousinH

AlfandariD

WhiteJM

2002 The cysteine-rich domain regulates ADAM protease function in vivo. J Cell Biol 159 893 902

20. AkiyamaM

TakedaS

KokameK

TakagiJ

MiyataT

2009 Crystal structures of the noncatalytic domains of ADAMTS13 reveal multiple discontinuous exosites for von Willebrand factor. Proc Natl Acad Sci U S A 106 19274 19279

21. CoulombeB

SkupD

1988 In vitro synthesis of the active tissue inhibitor of metalloproteinases encoded by a complementary DNA from virus-infected murine fibroblasts. J Biol Chem 263 1439 1443

22. DuanZ

LiFQ

WechslerJ

Meade-WhiteK

WilliamsK

2004 A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia. Mol Cell Biol 24 58 70

23. FautschMP

JohnsonDH

2001 Characterization of myocilin-myocilin interactions. Invest Ophthalmol Vis Sci 42 2324 2331

24. ZhengXL

WuHM

ShangD

FallsE

SkipwithCG

Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic thrombocytopenic purpura. Haematologica 95 1555 1562

25. SoejimaK

MatsumotoM

KokameK

YagiH

IshizashiH

2003 ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Blood 102 3232 3237

26. KellerKE

AgaM

BradleyJM

KelleyMJ

AcottTS

2009 Extracellular matrix turnover and outflow resistance. Exp Eye Res 88 676 682

27. KellerKE

BradleyJM

AcottTS

2009 Differential effects of ADAMTS-1, -4, and -5 in the trabecular meshwork. Invest Ophthalmol Vis Sci 50 5769 5777

28. DagoneauN

Benoist-LasselinC

HuberC

FaivreL

MegarbaneA

2004 ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet 75 801 806

29. MoralesJ

Al-SharifL

KhalilDS

ShinwariJM

BaviP

2009 Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet 85 558 568

30. FaivreL

GorlinRJ

WirtzMK

GodfreyM

DagoneauN

2003 In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet 40 34 36

31. FaivreL

DollfusH

LyonnetS

AlembikY

MegarbaneA

2003 Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am J Med Genet A 123A 204 207

32. RamirezF

SakaiLY

2009 Biogenesis and function of fibrillin assemblies. Cell Tissue Res 339 71 82

33. IzquierdoNJ

TraboulsiEI

EngerC

MaumeneeIH

1992 Glaucoma in the Marfan syndrome. Trans Am Ophthalmol Soc 90 111 117; discussion 118–122

34. DureauP

2008 Pathophysiology of zonular diseases. Curr Opin Ophthalmol 19 27 30

35. AhramD

SatoTS

KohilanA

TayehM

ChenS

2009 A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet 84 274 278

36. TektasOY

Lutjen-DrecollE

2009 Structural changes of the trabecular meshwork in different kinds of glaucoma. Exp Eye Res 88 769 775

37. SamuelsonDA

GumGG

GelattKN

1989 Ultrastructural changes in the aqueous outflow apparatus of beagles with inherited glaucoma. Invest Ophthalmol Vis Sci 30 550 561

38. TripathiRC

LiJ

ChanWF

TripathiBJ

1994 Aqueous humor in glaucomatous eyes contains an increased level of TGF-beta 2. Exp Eye Res 59 723 727

39. TammER

FuchshoferR

2007 What increases outflow resistance in primary open-angle glaucoma? Surv Ophthalmol 52 Suppl 2 S101 104

40. AliM

McKibbinM

BoothA

ParryDA

JainP

2009 Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet 84 664 671

41. SilbersteinM

TzemachA

DovgolevskyN

FishelsonM

SchusterA

2006 Online system for faster multipoint linkage analysis via parallel execution on thousands of personal computers. Am J Hum Genet 78 922 935

42. AbecasisGR

ChernySS

CooksonWO

CardonLR

2001 GRR: graphical representation of relationship errors. Bioinformatics 17 742 743

43. AlbertTJ

MollaMN

MuznyDM

NazarethL

WheelerD

2007 Direct selection of human genomic loci by microarray hybridization. Nat Methods 4 903 905

44. OkouDT

SteinbergKM

MiddleC

CutlerDJ

AlbertTJ

2007 Microarray-based genomic selection for high-throughput resequencing. Nat Methods 4 907 909

45. LangmeadB

TrapnellC

PopM

SalzbergSL

2009 Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10 R25

46. LiH

HandsakerB

WysokerA

FennellT

RuanJ

2009 The Sequence Alignment/Map format and SAMtools. Bioinformatics 25 2078 2079

47. RoyA

KucukuralA

ZhangY

2010 I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5 725 738

48. JonesTA

ZouJY

CowanSW

KjeldgaardM

1991 Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A 47 Pt 2 110 119

49. KraulisPJ

1991 Molscript - a Program to Produce Both Detailed and Schematic Plots of Protein Structures. Journal of Applied Crystallography 24 946 950

50. MerrittEA

BaconDJ

1997 Raster3D: photorealistic molecular graphics. Methods Enzymol 277 505 524