Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoform

PLoS Genet. 2010 Mar 19;6(3):e1000884. doi: 10.1371/journal.pgen.1000884.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / chemistry
  • ADP-Ribosylation Factors / deficiency
  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism*
  • Amino Acid Sequence
  • Animals
  • Bardet-Biedl Syndrome / complications
  • Bardet-Biedl Syndrome / genetics
  • Bardet-Biedl Syndrome / pathology
  • Bardet-Biedl Syndrome / physiopathology
  • Eye Abnormalities / complications
  • Eye Abnormalities / pathology
  • Eye Abnormalities / physiopathology
  • Ganglia / drug effects
  • Ganglia / metabolism
  • Ganglia / pathology
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Oligonucleotides, Antisense / pharmacology
  • Organ Specificity / drug effects
  • Phenotype
  • Photoreceptor Cells, Vertebrate / drug effects
  • Photoreceptor Cells, Vertebrate / metabolism
  • Photoreceptor Cells, Vertebrate / pathology
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Transport / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reflex, Startle / drug effects
  • Rod Opsins / metabolism
  • Vision, Ocular* / drug effects
  • Zebrafish
  • Zebrafish Proteins / chemistry
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Oligonucleotides, Antisense
  • Protein Isoforms
  • RNA, Messenger
  • Rod Opsins
  • Zebrafish Proteins
  • middle-wavelength opsin
  • ARL6 protein, human
  • ADP-Ribosylation Factors
  • ARL6 protein, zebrafish
  • Arl6 protein, mouse