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The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors.

Luhmann UF, Carvalho LS, Holthaus SM, Cowing JA, Greenaway S, Chu CJ, Herrmann P, Smith AJ, Munro PM, Potter P, Bainbridge JW, Ali RR - Hum. Mol. Genet. (2014)

Bottom Line: Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior retinal lesions that was strikingly variable between the lines.By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified.This study also provides insight into the nature of the retinal vascular lesions that likely represent a clinical correlate for the formation of retinal telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and u.luhmann@ucl.ac.uk.

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Retinal pathology of different Crb1rd8/rd8 mouse lines illustrated by corresponding TEFI, AF-SLO fundus images and sagittal OCT and semithin sections at 2 months of age. (A–D) Example images of the different modalities including superior and inferior images from homozygous Crb1rd8/rd8 mice from the respective lines. (A) Crb1rd8/rd8/J, (B, C) C57BL/6/Crb1rd8/rd8 (2), (D) C57BL/6/Crb1rd8/rd8 (1) and (E): C57BL/6J wild-type mice (Crb1+/+). White arrow heads indicate lesions affecting the structure of the ONL and the integrity of the OLM. White arrows indicate rosette formation observed in mice with severe manifestations of the phenotype. These lesions are preferentially located in the inferior retina and correspond well with autofluorescent lesions in AF-SLO fundus images and with white/opaque lesions in the fundus images obtained by TEFI. INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OLM, outer limiting membrane. Scale bar for semithin images: 50 μm.
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DDU424F2: Retinal pathology of different Crb1rd8/rd8 mouse lines illustrated by corresponding TEFI, AF-SLO fundus images and sagittal OCT and semithin sections at 2 months of age. (A–D) Example images of the different modalities including superior and inferior images from homozygous Crb1rd8/rd8 mice from the respective lines. (A) Crb1rd8/rd8/J, (B, C) C57BL/6/Crb1rd8/rd8 (2), (D) C57BL/6/Crb1rd8/rd8 (1) and (E): C57BL/6J wild-type mice (Crb1+/+). White arrow heads indicate lesions affecting the structure of the ONL and the integrity of the OLM. White arrows indicate rosette formation observed in mice with severe manifestations of the phenotype. These lesions are preferentially located in the inferior retina and correspond well with autofluorescent lesions in AF-SLO fundus images and with white/opaque lesions in the fundus images obtained by TEFI. INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OLM, outer limiting membrane. Scale bar for semithin images: 50 μm.

Mentions: Topical endoscopic fundal imaging (TEFI), AF-SLO, optical coherence tomography (OCT) and semithin histology revealed that this pathology was mainly confined to the inferior retina of Crb1rd8/rd8 mice (Fig. 2). White/opaque and autofluorescent fundus lesions correlated well with the position of lesions in OCT images at the outer plexiform layer (OPL) and in the outer nuclear layer (ONL) (Fig. 2A–C). Corresponding rosette formation (Fig. 2A and B, white arrows) and drop out and disruption of photoreceptor columns (Fig. 2A–C, arrow heads) were observed in sagittal semithin sections of prominently affected Crb1rd8/rd8 mice. However, not all Crb1rd8/rd8 mice showed these inferior lesions by TEFI or AF-SLO. In particular, in the C57BL/6/Crb1rd8/rd8 (1) mice only small inferior lesions were visible (Fig. 2D) that were very difficult to identify in OCT and semithin sections (Fig. 2D) since these appeared to be very similar to those from wild-type mice (Fig. 2E).Figure 2.


The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors.

Luhmann UF, Carvalho LS, Holthaus SM, Cowing JA, Greenaway S, Chu CJ, Herrmann P, Smith AJ, Munro PM, Potter P, Bainbridge JW, Ali RR - Hum. Mol. Genet. (2014)

Retinal pathology of different Crb1rd8/rd8 mouse lines illustrated by corresponding TEFI, AF-SLO fundus images and sagittal OCT and semithin sections at 2 months of age. (A–D) Example images of the different modalities including superior and inferior images from homozygous Crb1rd8/rd8 mice from the respective lines. (A) Crb1rd8/rd8/J, (B, C) C57BL/6/Crb1rd8/rd8 (2), (D) C57BL/6/Crb1rd8/rd8 (1) and (E): C57BL/6J wild-type mice (Crb1+/+). White arrow heads indicate lesions affecting the structure of the ONL and the integrity of the OLM. White arrows indicate rosette formation observed in mice with severe manifestations of the phenotype. These lesions are preferentially located in the inferior retina and correspond well with autofluorescent lesions in AF-SLO fundus images and with white/opaque lesions in the fundus images obtained by TEFI. INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OLM, outer limiting membrane. Scale bar for semithin images: 50 μm.
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Related In: Results  -  Collection

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DDU424F2: Retinal pathology of different Crb1rd8/rd8 mouse lines illustrated by corresponding TEFI, AF-SLO fundus images and sagittal OCT and semithin sections at 2 months of age. (A–D) Example images of the different modalities including superior and inferior images from homozygous Crb1rd8/rd8 mice from the respective lines. (A) Crb1rd8/rd8/J, (B, C) C57BL/6/Crb1rd8/rd8 (2), (D) C57BL/6/Crb1rd8/rd8 (1) and (E): C57BL/6J wild-type mice (Crb1+/+). White arrow heads indicate lesions affecting the structure of the ONL and the integrity of the OLM. White arrows indicate rosette formation observed in mice with severe manifestations of the phenotype. These lesions are preferentially located in the inferior retina and correspond well with autofluorescent lesions in AF-SLO fundus images and with white/opaque lesions in the fundus images obtained by TEFI. INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OLM, outer limiting membrane. Scale bar for semithin images: 50 μm.
Mentions: Topical endoscopic fundal imaging (TEFI), AF-SLO, optical coherence tomography (OCT) and semithin histology revealed that this pathology was mainly confined to the inferior retina of Crb1rd8/rd8 mice (Fig. 2). White/opaque and autofluorescent fundus lesions correlated well with the position of lesions in OCT images at the outer plexiform layer (OPL) and in the outer nuclear layer (ONL) (Fig. 2A–C). Corresponding rosette formation (Fig. 2A and B, white arrows) and drop out and disruption of photoreceptor columns (Fig. 2A–C, arrow heads) were observed in sagittal semithin sections of prominently affected Crb1rd8/rd8 mice. However, not all Crb1rd8/rd8 mice showed these inferior lesions by TEFI or AF-SLO. In particular, in the C57BL/6/Crb1rd8/rd8 (1) mice only small inferior lesions were visible (Fig. 2D) that were very difficult to identify in OCT and semithin sections (Fig. 2D) since these appeared to be very similar to those from wild-type mice (Fig. 2E).Figure 2.

Bottom Line: Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1(rd8/rd8) lines showed a significant increase in the number of inferior retinal lesions that was strikingly variable between the lines.By whole-genome SNP analysis of the genotype-phenotype correlation, a candidate region on chromosome 15 was identified.This study also provides insight into the nature of the retinal vascular lesions that likely represent a clinical correlate for the formation of retinal telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and u.luhmann@ucl.ac.uk.

Show MeSH
Related in: MedlinePlus