| First Author | Chang B | Year | 2024 |
| Journal | MGI Direct Data Submission | Mgi Jnum | J:347903 |
| Mgi Id | MGI:7628690 | Citation | Chang B (2024) B6.Cg-rd22/BOC strain details. MGI Direct Data Submission |
| abstractText | The retinal degeneration 22 (rd22) heritable mutant phenotype was discovered in our ocular phenotypes screening program in March 2018 in a male mouse of strain STOCK Atp13a2tm1.1Wtd/J (JAX Stock No. 028387) that presented with vessel attenuation and retinal degeneration as well as no light adapted ERG responses at 1 month of age. We mated the mutant male mouse with C57BL/6J and all F1 mice had normal retinas. The retinal degeneration phenotype was recovered in the F2 generation, and we named this recessive mutation retinal degeneration 22 (rd22). Then we made a congenic strain B6.Cg-rd22/Boc (JAX Stock No. 036966) by backcrossing the rd22 phenotype onto C57BL/6J for 5 generations of backcross-intercross mating then sibling mating to homozygosity. These rd22 mice also had no light adapted ERG responses as early as 1 month of age (Figure 1). The amplitudes of dark adapted ERG responses were decreased with age. Fundus and OCT showed retinal degeneration (Figure 1). Histology revealed a significant reduction of cone photoreceptors as well as mislocalization of rod photoreceptors to the inner nuclear layer (Figure 1). Linkage crosses showed this spontaneous mutation to be an autosomal recessive mutation that mapped to Chromosome 12 between D12Mit158 and D12Mit133, where the mouse tubulin tyrosine ligase-like family, member 5 (Ttll5) gene is located. Mutations in the human TTLL5 gene cause cone-rod dystrophy-19 (CORD19, OMIM #615860). There are two major transcripts reported in mouse, Ttll5-201 and Ttll5-202. Ttll5-201 has 34 exons with a longer 3-prime UTR (618 bp) and Ttll5-202 has 33 exons (exon 33 skipped) with a shorter 3-prime UTR (43 bp). By mouse retinal cDNA sequence analysis of wild-type mice, we found that the mouse retina uses the Ttll5-202 transcript with a longer 3-prime UTR. While no mutation was identified in the 5-prime upstream sequence or the coding regions of the Ttll5 gene by cDNA sequence from rd22 retinal transcripts, a G to T base substitution was found in the 5th base pair of the 3-prime UTR along with a duplication of 122 bp beginning at the 6th base pair of the 3-prime UTR. Although the exact mutation, perhaps in a non-coding regulatory region, has yet to be defined, the rd22 mouse is a valuable model for the studies of the pathological mechanism for human cone-rod dystrophy such as CORD19. The human disease resulting from TTLL5 mutations has prominent cone photoreceptor involvement and is clinically characterized as cone-rod dystrophy or cone dystrophy; the disease phenotype is very similar to that of the rd22 mouse. Initial studies of a Ttll5 knockout (Ttll5-/-) mouse, which deleted exons 23 and 24, did not find an overt retinal defect based on histology. However, in a later NEI study, Ttll5-/- mice were reported to develop a late-onset, slowly progressive form of photoreceptor degeneration, with mislocalization of both rhodopsin and cone opsin at older ages (Sun X., et al 2016). Mice homozygous for this Ttll5 allele exhibited male infertility associated with abnormal sperm morphology and reduced tubulin polyglutamylation in the spermatozoa. Based on human studies, nonsense mutations in TTLL5 gene cause late-onset and slow progressive photoreceptor degeneration and male infertility (Bedoni N., et al 2016), similar to the phenotype of the Ttll5 knockout mice, whereas a missense mutation in TTLL5 causes an early-onset cone-rod dystrophy and has no effect on male fertility (Bedoni N., et al), similar to our rd22 mutant mice. The rd22 mice appear to have normal fertility. |
