Identification and Functional Analysis of the Vision-Specific BBS3 (ARL6) Long Isoform

English version České info

Bardet-Biedl Syndrome (BBS) is a heterogeneous syndromic form of retinal degeneration. We have identified a novel transcript of a known BBS gene, BBS3 (ARL6), which includes an additional exon. This transcript, BBS3L, is evolutionally conserved and is expressed predominantly in the eye, suggesting a specialized role in vision. Using antisense oligonucleotide knockdown in zebrafish, we previously demonstrated that bbs3 knockdown results in the cardinal features of BBS in zebrafish, including defects to the ciliated Kupffer's Vesicle and delayed retrograde melanosome transport. Unlike bbs3, knockdown of bbs3L does not result in Kupffer's Vesicle or melanosome transport defects, rather its knockdown leads to impaired visual function and mislocalization of the photopigment green cone opsin. Moreover, BBS3L RNA, but not BBS3 RNA, is sufficient to rescue both the vision defect as well as green opsin localization in the zebrafish retina. In order to demonstrate a role for Bbs3L function in the mammalian eye, we generated a Bbs3L-null mouse that presents with disruption of the normal photoreceptor architecture. Bbs3L-null mice lack key features of previously published Bbs-null mice, including obesity. These data demonstrate that the BBS3L transcript is required for proper retinal function and organization.

Vyšlo v časopise: Identification and Functional Analysis of the Vision-Specific BBS3 (ARL6) Long Isoform. PLoS Genet 6(3): e32767. doi:10.1371/journal.pgen.1000884
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000884

Souhrn

Zdroje

1. GreenJS

ParfreyPS

HarnettJD

FaridNR

CramerBC

1989 The cardinal manifestations of Bardet-Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. N Engl J Med 321 1002 1009

2. HarnettJD

GreenJS

CramerBC

JohnsonG

ChafeL

1988 The spectrum of renal disease in Laurence-Moon-Biedl syndrome. N Engl J Med 319 615 618

3. BardetG

1995 On congenital obesity syndrome with polydactyly and retinitis pigmentosa (a contribution to the study of clinical forms of hypophyseal obesity). 1920. Obes Res 3 387 399

4. BiedlA

1995 A pair of siblings with adiposo-genital dystrophy. 1922. Obes Res 3 404

5. ElbedourK

ZuckerN

ZalzsteinE

BarkiY

CarmiR

1994 Cardiac abnormalities in the Bardet-Biedl syndrome: echocardiographic studies of 22 patients. Am J Med Genet 52 164 169

6. LeysMJ

SchreinerLA

HansenRM

MayerDL

FultonAB

1988 Visual acuities and dark-adapted thresholds of children with Bardet-Biedl syndrome. Am J Ophthalmol 106 561 569

7. RiiseR

1987 Visual function in Laurence-Moon-Bardet-Biedl syndrome. A survey of 26 cases. Acta Ophthalmol Suppl 182 128 131

8. JacobsonSG

BorruatFX

ApathyPP

1990 Patterns of rod and cone dysfunction in Bardet-Biedl syndrome. Am J Ophthalmol 109 676 688

9. BealesPL

WarnerAM

HitmanGA

ThakkerR

FlinterFA

1997 Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families. J Med Genet 34 92 98

10. CarmiR

ElbedourK

StoneEM

SheffieldVC

1995 Phenotypic differences among patients with Bardet-Biedl syndrome linked to three different chromosome loci. Am J Med Genet 59 199 203

11. RiiseR

AndreassonS

BorgastromMK

WrightAF

TommerupN

1997 Intrafamilial variation of the phenotype in Bardet-Biedl syndrome. Br J Ophthalmol 81 378 385

12. FultonAB

HansenRM

GlynnRJ

1993 Natural course of visual functions in the Bardet-Biedl syndrome. Arch Ophthalmol 111 1500 1506

13. HeonE

WestallC

CarmiR

ElbedourK

PantonC

2005 Ocular phenotypes of three genetic variants of Bardet-Biedl syndrome. Am J Med Genet A 132A 283 287

14. MykytynK

NishimuraDY

SearbyCC

ShastriM

YenHJ

2002 Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet 31 435 438

15. NishimuraDY

SearbyCC

CarmiR

ElbedourK

Van MaldergemL

2001 Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2). Hum Mol Genet 10 865 874

16. ChiangAP

NishimuraD

SearbyC

ElbedourK

CarmiR

2004 Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3). Am J Hum Genet 75 475 484

17. FanY

EsmailMA

AnsleySJ

BlacqueOE

BoroevichK

2004 Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet 36 989 993

18. MykytynK

BraunT

CarmiR

HaiderNB

SearbyCC

2001 Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet 28 188 191

19. LiJB

GerdesJM

HaycraftCJ

FanY

TeslovichTM

2004 Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117 541 552

20. KatsanisN

BealesPL

WoodsMO

LewisRA

GreenJS

2000 Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nat Genet 26 67 70

21. SlavotinekAM

StoneEM

MykytynK

HeckenlivelyJR

GreenJS

2000 Mutations in MKKS cause Bardet-Biedl syndrome. Nat Genet 26 15 16

22. BadanoJL

AnsleySJ

LeitchCC

LewisRA

LupskiJR

2003 Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet 72 650 658

23. AnsleySJ

BadanoJL

BlacqueOE

HillJ

HoskinsBE

2003 Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425 628 633

24. NishimuraDY

SwiderskiRE

SearbyCC

BergEM

FergusonAL

2005 Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am J Hum Genet 77 1021 1033

25. StoetzelC

LaurierV

DavisEE

MullerJ

RixS

2006 BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 38 521 524

26. ChiangAP

BeckJS

YenHJ

TayehMK

ScheetzTE

2006 Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci U S A 103 6287 6292

27. StoetzelC

MullerJ

LaurierV

DavisEE

ZaghloulNA

2007 Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am J Hum Genet 80 1 11

28. LeitchCC

ZaghloulNA

DavisEE

StoetzelC

Diaz-FontA

2008 Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet 40 443 448

29. MykytynK

MullinsRF

AndrewsM

ChiangAP

SwiderskiRE

2004 Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proc Natl Acad Sci U S A 101 8664 8669

30. NishimuraDY

FathM

MullinsRF

SearbyC

AndrewsM

2004 Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proc Natl Acad Sci U S A 101 16588 16593

31. FathMA

MullinsRF

SearbyC

NishimuraDY

WeiJ

2005 Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome. Hum Mol Genet 14 1109 1118

32. DavisRE

SwiderskiRE

RahmouniK

NishimuraDY

MullinsRF

2007 A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. Proc Natl Acad Sci U S A 104 19422 19427

33. YoungRW

1967 The renewal of photoreceptor cell outer segments. J Cell Biol 33 61 72

34. BesharseJC

HorstCJ

1990 The photoreceptor connecting cilium. A model for for the transition zone.

BloodgoodRA

Ciliary and Flagellar Membranes New York Plenum Publishing Corp 389 417

35. KrockBL

PerkinsBD

2008 The intraflagellar transport protein IFT57 is required for cilia maintenance and regulates IFT-particle-kinesin-II dissociation in vertebrate photoreceptors. J Cell Sci 121 1907 1915

36. PazourGJ

BakerSA

DeaneJA

ColeDG

DickertBL

2002 The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenance. J Cell Biol 157 103 113

37. Luby-PhelpsK

FogertyJ

BakerSA

PazourGJ

BesharseJC

2008 Spatial distribution of intraflagellar transport proteins in vertebrate photoreceptors. Vision Res 48 413 423

38. TsujikawaM

MalickiJ

2004 Intraflagellar transport genes are essential for differentiation and survival of vertebrate sensory neurons. Neuron 42 703 716

39. SukumaranS

PerkinsBD

2009 Early defects in photoreceptor outer segment morphogenesis in zebrafish ift57, ift88 and ift172 Intraflagellar Transport mutants. Vision Res 49 479 489

40. Abd-El-BarrMM

SykoudisK

AndrabiS

EichersER

PennesiME

2007 Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet-Biedl syndrome. Vision Res 47 3394 3407

41. SwiderskiRE

NishimuraDY

MullinsRF

OlveraMA

RossJL

2007 Gene expression analysis of photoreceptor cell loss in bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damage. Invest Ophthalmol Vis Sci 48 3329 3340

42. YenHJ

TayehMK

MullinsRF

StoneEM

SheffieldVC

2006 Bardet-Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer's vesicle cilia function. Hum Mol Genet 15 667 677

43. TayehMK

YenHJ

BeckJS

SearbyCC

WestfallTA

2008 Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning. Hum Mol Genet

44. BlacqueOE

ReardonMJ

LiC

McCarthyJ

MahjoubMR

2004 Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev 18 1630 1642

45. PasqualatoS

RenaultL

CherfilsJ

2002 Arf, Arl, Arp and Sar proteins: a family of GTP-binding proteins with a structural device for 'front-back' communication. EMBO Rep 3 1035 1041

46. HuM

EasterSS

1999 Retinal neurogenesis: the formation of the initial central patch of postmitotic cells. Dev Biol 207 309 321

47. SkoldHN

AspengrenS

WallinM

2002 The cytoskeleton in fish melanophore melanosome positioning. Microsc Res Tech 58 464 469

48. BarralDC

SeabraMC

2004 The melanosome as a model to study organelle motility in mammals. Pigment Cell Res 17 111 118

49. MarksMS

SeabraMC

2001 The melanosome: membrane dynamics in black and white. Nat Rev Mol Cell Biol 2 738 748

50. BlottEJ

GriffithsGM

2002 Secretory lysosomes. Nat Rev Mol Cell Biol 3 122 131

51. NascimentoAA

RolandJT

GelfandVI

2003 Pigment cells: a model for the study of organelle transport. Annu Rev Cell Dev Biol 19 469 491

52. SchmittEA

DowlingJE

1999 Early retinal development in the zebrafish, Danio rerio: light and electron microscopic analyses. J Comp Neurol 404 515 536

53. EasterSSJr

NicolaGN

1996 The development of vision in the zebrafish (Danio rerio). Dev Biol 180 646 663

54. BranchekT

1984 The development of photoreceptors in the zebrafish, brachydanio rerio. II. Function. J Comp Neurol 224 116 122

55. LiuY

ShenY

RestJS

RaymondPA

ZackDJ

2001 Isolation and characterization of a zebrafish homologue of the cone rod homeobox gene. Invest Ophthalmol Vis Sci 42 481 487

56. ShenYC

RaymondPA

2004 Zebrafish cone-rod (crx) homeobox gene promotes retinogenesis. Dev Biol 269 237 251

57. MasaiI

LeleZ

YamaguchiM

KomoriA

NakataA

2003 N-cadherin mediates retinal lamination, maintenance of forebrain compartments and patterning of retinal neurites. Development 130 2479 2494

58. VihtelicTS

DoroCJ

HydeDR

1999 Cloning and characterization of six zebrafish photoreceptor opsin cDNAs and immunolocalization of their corresponding proteins. Vis Neurosci 16 571 585

59. BilottaJ

SaszikS

SutherlandSE

2001 Rod contributions to the electroretinogram of the dark-adapted developing zebrafish. Dev Dyn 222 564 570

60. YoungRW

1985 Cell differentiation in the retina of the mouse. Anat Rec 212 199 205

61. Abu SafiehL

AldahmeshM

ShamseldinH

HashemM

ShaheenR

2009 Clinical and Molecular Characterization of Bardet-Biedl Syndrome in Consanguineous Populations: The Power of Homozygosity Mapping. J Med Genet