Dataset Information

FAM161A and TTC8 are Differentially Expressed in Non-Allelelic Early Onset Retinal Degeneration.

ABSTRACT: Ciliary genes FAM161A and TTC8 have been implicated in retinal degeneration (RD) in humans and in dogs. The identification of FAM161A and TTC8 mutations in canine RD is exciting as there is the potential to develop novel large animal models for RD. However, the disease phenotypes in the dog and the roles of abnormal genes in disease pathology have yet to be fully characterized. The present study evaluated the expression patterns of FAM161A and TTC8 during normal retinal development in dogs, and in three non-allelic, early onset canine RD models at critical time points of the disease: RCD1, XLPRA2 and ERD. Both genes were differentially expressed in RCD1 and ERD, but not in XLPRA2. These results add evidence to the hypothesis that (a) mutations in many retinal genes have a cascade effect on the expression of multiple, possibly unrelated genes and (b) a large number and wide range of genes probably contribute to RD in general.

SUBMITTER: Downs LM

PROVIDER: S-EPMC4602411 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

FAM161A and TTC8 are Differentially Expressed in Non-Allelelic Early Onset Retinal Degeneration.

Downs Louise M LM Aguirre Gustavo D GD

Advances in experimental medicine and biology 20160101

Ciliary genes FAM161A and TTC8 have been implicated in retinal degeneration (RD) in humans and in dogs. The identification of FAM161A and TTC8 mutations in canine RD is exciting as there is the potential to develop novel large animal models for RD. However, the disease phenotypes in the dog and the roles of abnormal genes in disease pathology have yet to be fully characterized. The present study evaluated the expression patterns of FAM161A and TTC8 during normal retinal development in dogs, and ...[more]

PMID: 26427412

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Project description:Mutations in the Membrane-type frizzled related protein (Mfrp) gene results in an early-onset retinal degeneration associated with retinitis pigmentosa, microphthalmia, optic disc drusen and foveal schisis. In the current study, a previously characterized mouse model of human retinal degeneration carrying homozygous c.498_499insC mutations in Mfrp (MfrpKI/KI) was used. Patients carrying this mutation have retinal degeneration at an early age. The model demonstrates subretinal deposits and develops early-onset photoreceptor degeneration. We observed large subretinal deposits in MfrpKI/KI mice which were strongly CD68 positive and co-localized with autofluorescent spots. Single cell RNA sequencing of MfrpKI/KI mice retinal microglia showed a significantly higher number of pan-macrophage marker Iba-1 and F4/80 positive cells with increased expression of activation marker (CD68) and lowered microglial homeostatic markers (TMEM119, P2ry13, P2ry13, Siglech) compared with wild type mice confirming microglial activation as observed in retinal immunostaining showing microglia activation in subretinal region. Trajectory analysis identified a small cluster of microglial cells with activation transcriptomic signatures that could represent a subretinal microglia population in MfrpKI/KI mice expressing higher levels of APOE. We validated these findings using immunofluorescence staining of retinal cryosections and found a significantly higher number of subretinal Iba-1/ApoE positive microglia in MfrpKI/KI mice with some subretinal microglia also expressing lowered levels of microglial homeostatic marker TMEM119, confirming microglial origin. In summary, we confirm that MfrpKI/KI mice carrying the c.498_499insC mutation had a significantly higher population of activated microglia in their retina with distinct subsets of subretinal microglia. Further, studies are required to confirm whether the association of increased subretinal microglia in MfrpKI/KI mice are causal in degeneration.

Dataset Information

FAM161A and TTC8 are Differentially Expressed in Non-Allelelic Early Onset Retinal Degeneration.

Publications

FAM161A and TTC8 are Differentially Expressed in Non-Allelelic Early Onset Retinal Degeneration.

Similar Datasets

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