Conditional loss of Spata7 in photoreceptors causes progressive retinal degeneration in mice.

The mammalian retina consists of multiple cell layers including photoreceptor cells, which are light sensing neurons that play essential functions in the visual process. Previously, we identified mutations in SPATA7, encoding spermatogenesis associated protein 7, in families with Leber Congenital Amaurosis (LCA) and juvenile Retinitis Pigmentosa (RP), and showed that Spata7 null mice recapitulate the human disease phenotype of retinal degeneration. SPATA7 is expressed in the connecting cilium of photoreceptor (PR) cells in the mouse retina, as well as in retinal pigment epithelium (RPE) cells, but the functional role of Spata7 in the RPE remains unknown. To investigate whether Spata7 is required in PRs, the RPE, or both, we conditionally knocked out Spata7 in photoreceptors and RPE cells using Crx-Cre and Best1-Cre transgenic mouse lines, respectively. In Spata7 photoreceptor-specific conditional (cKO) mice, both rod and cone photoreceptor dysfunction and degeneration is observed, characterized by progressive thinning of the outer nuclear layer and reduced response to light; however, RPE-specific deletion of Spata7 does not impair retinal function or cell survival. Furthermore, our findings show that both Rhodopsin and RPGRIP1 are mislocalized in the Spata7Flox/-; Crx-Cre cKO mice, suggesting that loss of Spata7 in photoreceptors alone can result in altered trafficking of these proteins in the connecting cilium. Together, our findings suggest that loss of Spata7 in photoreceptors alone is sufficient to cause photoreceptor degeneration, but its function in the RPE is not required for photoreceptor survival; therefore, loss of Spata7 in photoreceptors alters both rod and cone function and survival, consistent with the clinical phenotypes observed in LCA and RP patients with mutations in SPATA7.

Phenotypic expansion and progression of SPATA7-associated retinitis pigmentosa.

PURPOSE: To report an unusual phenotype of retinitis pigmentosa (RP) caused by compound heterozygous mutations in SPATA7, and describe the progression over a two year follow-up period. METHODS: Retrospective case study. RESULTS: A 63-year-old man with a long history of nyctalopia, progressive visual field constriction, and a recent subacute decrease in visual acuity of the left eye presented for evaluation of a suspected retinal degeneration. Multimodal retinal imaging and functional assessment with full-field electroretinogram suggested a severe rod-cone dysfunction masquerading as a choroideremia-like phenotype. A vitreous opacity was found to explain recent changes in the left eye and a 25-guage vitrectomy and membrane peel was performed, yielding no change in visual acuity. Whole-exome sequencing revealed compound heterozygous variants in SPATA7 that were predicted to be pathogenic. CONCLUSIONS: Compound heterozygous c.1100A > G, p.(Y367C) and c.1102_1103delCT, p.(L368Efs*4) variants in SPATA7 manifest as an unusual RP phenotype in this case, showing extensive choroidal sclerosis and retinal pigment epithelium (RPE) atrophy with evidence of progression over two years on multimodal imaging.

The spermatogenesis-associated protein-7 (SPATA7) gene - an overview.

BACKGROUND: The spermatogenesis-associated protein-7 (SPATA7) gene encodes a ciliary protein that is expressed in the photoreceptors and in spermatocytes. Mutations in the SPATA7 gene are associated with congenital and early-onset forms of retinal dystrophy. METHODS: Papers and review articles on SPATA7 were retrieved from the PubMed database using the search terms "SPATA7" and "spermatogenesis-associated protein 7". Those that were relevant to retinal disease or to the function of the SPATA7 gene were selected for review. RESULTS: The SPATA7 locus was mapped as LCA3 to chromosome 14, and the gene identified by screening of all genes in the refined genomic interval. Mutations in SPATA7 are associated with Leber congenital amaurosis (LCA) and early-onset retinitis pigmentosa. There are no clear-cut correlations between the genotypes and phenotypes in SPATA7-associated disease, and phenotypic heterogeneity occurs among patients with the same mutation. The SPATA7 protein is expressed in the photoreceptor connecting cilia. Murine models of Spata7 knockout have been useful in understanding the role of this gene in the retina at the cellular and molecular levels. CONCLUSION: Most of the mutations in the SPATA7 are nonsense or frameshifts and are predicted to lead to loss of function. Clinical heterogeneity is often seen in patients with SPATA7 mutations. Animal models of SPATA7 knockout indicate that the protein has a key role in organizing the ciliary protein complexes.