Alternative titles; symbols
HGNC Approved Gene Symbol: SPATA7
Cytogenetic location: 14q31.3 Genomic coordinates (GRCh38) : 14:88,385,657-88,470,350 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q31.3 | Leber congenital amaurosis 3 | 604232 | Autosomal recessive | 3 |
| Retinitis pigmentosa 94, variable age at onset, autosomal recessive | 604232 | Autosomal recessive | 3 |
Using differential display PCR analysis, Zhang et al. (2003) identified rat SPATA7. By EST database analysis and screening of human testis library panels by RT-PCR, they identified full-length human SPATA7. SPATA7 encodes a 599-amino acid protein containing several DNA-binding sites and 3 phosphorylation sites. The human and rat SPATA7 proteins share 77% sequence identity. Northern blot analysis of rat tissues showed testis-specific expression, which was first detected at postnatal day 30. Immunohistochemistry of rat testis localized SPATA7 to primary spermatocytes in early prophase of meiosis I.
Wang et al. (2009) found that, in addition to its expression in testis, Spata7 is expressed in multiple layers of the mature mouse retina with uniform distribution in the cytoplasm of the inner segment.
To establish the cellular location of SPATA7, Eblimit et al. (2015) expressed epitope-tagged SPATA7 in hTERT RPE1 cells and observed expression in the microtubule network, with localization to the ciliary axoneme of ciliated cells. Immunostained mouse retinal sections showed progressively increasing immunoreactivity, with SPATA7 first clearly detected at postnatal day 4 (P4), coinciding with developing photoreceptors. At P15, the strongest SPATA7 immunoreactivity was observed in the photoreceptor cell layer, specifically localizing at the connecting cilium between the inner and outer segments of both rod and cone photoreceptor cells.
By immunostaining in mice, Eblimit et al. (2018) confirmed localization of Spata7 to the connection cilium in the retina.
Zhang et al. (2003) determined that the SPATA7 gene contains at least 12 exons spanning 52.8 kb.
By sequence analysis, Zhang et al. (2003) mapped the SPATA7 gene to chromosome 14q31.3.
Using a GAL4 (602518)-based yeast 2-hybrid system to screen a human retinal cDNA library, Eblimit et al. (2015) detected interaction between SPATA7 and RPGRIP1 (605446). In HEK293T cells, a bimolecular fluorescence complementation assay indicated that SPATA7 and RPGRIP1 localize in very close proximity to each other. In vivo interaction of the 2 proteins was confirmed by coimmunoprecipitation studies in mouse retinal tissue. In addition, GST pull-down assay in bovine and mouse retinal extracts showed that GST-SPATA7 was able to pull down endogenous RPGRIP1, and further studies demonstrated that SPATA7 binds to the coiled-coil domain of RPGRIP1. In the retina of Spata7-null mice, a substantial reduction in RPGRIP1 levels at the connecting cilium of photoreceptor cells with mislocalization to the inner segment was observed, suggesting that SPATA7 is required for the stable assembly and localization of the ciliary RPGRIP1 protein complex. The accumulation of rhodopsin (RHO; 180380) in the inner segments and around the nucleus of photoreceptors indicated a role for the complex in protein trafficking across the connecting cilium to the outer segments.
Leber Congenital Amaurosis 3
In a Saudi Arabian family with Leber congenital amaurosis (LCA3; 604232), previously reported by Li et al. (2009) (family KKESH-060), Wang et al. (2009) identified a homozygous mutation in the SPATA7 gene (R108X; 609868.0001) that segregated with the disease and was not found in 50 Saudi Arabian and 100 European samples. Mutation analysis in additional patients revealed homozygosity for the same R108X mutation in a Dutch LCA patient as well as a frameshift mutation in another LCA patient of Middle Eastern origin (609868.0002). Wang et al. (2009) also identified homozygous SPATA7 mutations in 2 patients with juvenile-onset retinitis pigmentosa (see later).
Mackay et al. (2011) screened all coding exons in the SPATA7 gene in 141 patients diagnosed with LCA or early childhood-onset severe retinal dystrophy and identified 4 disease-causing mutations in 5 families. They concluded that mutations in SPATA7 are a rare cause of childhood retinal dystrophy, accounting for 1.7% of disease in their cohort. Four consanguineous families with LCA, 3 of Pakistani and 1 of Bangladeshi origin, had a homozygous mutation in exon 5 (609868.0007) or exon 8 (609868.0002). In 1 nonconsanguineous British Caucasian family, 2 brothers had compound heterozygous mutations in exon 5 (609868.0005-609868.0006). One of the brothers had clinical features consistent with LCA, having severe visual loss from early infancy, pendular nystagmus, and sluggish pupillary responses. His brother had a milder phenotype with onset of nystagmus at 8 weeks of age. He was able to fix and follow at this age. When older, he was noted to have severe nyctalopia and constricted visual fields. These symptoms deteriorated significantly from 14 years of age.
Retinitis Pigmentosa 94, Variable Age at Onset
In 2 patients with juvenile-onset retinitis pigmentosa (RP94; see 604232), Wang et al. (2009) identified homozygosity for 2 different different nonsense and frameshift mutations in the SPATA7 gene (609868.0003 and 609868.0004, respectively). Wang et al. (2009) noted that, consistent with the observation that LCA has a more severe clinical phenotype than juvenile RP, the nonsense mutations associated with LCA are located in the middle of the SPATA7 coding region, whereas those associated with juvenile RP are located in the last 2 exons of SPATA7.
In 2 Spanish sibs from a consanguineous family with typical late-onset RP mapping to the SPATA7 locus on chromosome 14, Avila-Fernandez et al. (2011) identified homozygosity for the R85X mutation in the SPATA7 gene (609868.0007), previously reported in affected individuals from 3 families with LCA (Mackay et al., 2011). Avila-Fernandez et al. (2011) suggested that the phenotypic variability might be explained by modifier alleles contributing to penetrance and expressivity, or intronic variants influencing severity.
In a 21-year-old Hispanic man with retinal degeneration that had progressed over 12 years from a cone-rod dystrophy phenotype to a late-stage RP phenotype, Matsui et al. (2016) screened 163 retinal disease-associated genes and identified homozygosity for a 1-bp deletion in the SPATA7 gene (609868.0008).
In a 63-year-old man who had RP associated with prominent RPE atrophy and choroidal sclerosis, Sengillo et al. (2018) performed whole-exome sequencing and identified compound heterozygosity for mutations in the SPATA7 gene: a missense mutation (Y367C; 609868.0009) and a 2-bp deletion (609868.0010). The authors stated that future studies were needed to discern whether unidentified genetic modifiers were involved or whether this represented a phenotypic subset of SPATA7-associated retinal degeneration.
In a German brother and sister with retinal degeneration, diagnosed with rod-cone and cone-rod dystrophy, respectively, Feldhaus et al. (2018) analyzed genomic DNA using a panel of 286 retinal disease-associated genes and identified homozygosity for a missense mutation in the SPATA7 gene (I371T; 609868.0011). The variant, which was found at low minor allele frequency in the ExAC database, was present in heterozygosity in their unaffected 85-year-old mother; DNA was unavailable from the father. The authors noted that although the sibs were homozygous for the same mutation, they exhibited phenotypic variability, and thus genotype/phenotype correlation remained difficult.
Eblimit et al. (2015) generated Spata7-knockout mice and observed severe early-onset retinal defects, with a marked reduction in the thickness of the outer nuclear layer compared to wildtype mice. The loss in thickness was progressive, suggesting that photoreceptor cells degenerate in the absence of Spata7 function; other cell types in the mutant retinas were unaffected. Quantification of cone and rod cells per unit area indicated that cone photoreceptor degeneration proceeds at a substantially lower rate compared to rods in Spata7-mutant retinas. Transmission electron microscopy revealed shortened outer segments and disorganization of the disc membranes in mutant retinas compared to wildtype retinas, where the discs were well-organized into stacks. Analysis of rod and cone electroretinography (ERG) responses in the Spata7-null mice showed a decline in rod responses by postnatal day (P) 15 that became more pronounced with age, whereas cone-mediated responses showed only a slight age-dependent decline. Rod function was almost undetectable by age 12 months.
Eblimit et al. (2018) generated a conditional SPATA7-knockout allele to determine which cell type requires Spata7 function for photoreceptor survival. In Spata7 photoreceptor-specific conditional knockout mice, both rod and cone photoreceptor dysfunction and degeneration was observed, characterized by progressive thinning of the outer nuclear layer and reduced response to light. However, RPE-specific deletion of Spata7 did not impair retinal function or cell survival. The authors noted that the alteration in both rod and cone function resulting from loss of Spata7 in photoreceptors was consistent with the clinical phenotypes of LCA and RP observed in patients with SPATA7 mutations.
In 3 affected members of a Saudi Arabian family (KKESH-060) with Leber congenital amaurosis (LCA3; 604232) and a Dutch LCA patient, Wang et al. (2009) identified homozygosity for a 322C-T transition in exon 5 of the SPATA7 gene, resulting in an arg108-to-ter (R108X) substitution. The mutation segregated with disease and was not found in 50 Saudi Arabian or 100 European samples.
In a patient of Middle Eastern origin with Leber congenital amaurosis (LCA3; 604232), Wang et al. (2009) identified homozygosity for a 1-bp duplication (961dupA) in exon 8 of the SPATA7 gene, predicted to cause a frameshift and premature termination of the protein. The mutation was not found in 50 Saudi Arabian or 100 European samples.
Mackay et al. (2011) identified homozygosity for the 961dupA mutation in all affected members of a consanguineous Pakistani family segregating LCA3.
In a Portuguese patient with juvenile-onset retinitis pigmentosa (RP94; see 604232), Wang et al. (2009) identified homozygosity for a 1183C-T transition in exon 11 of the SPATA7 gene, resulting in an arg395-to-ter (R395X) substitution. The mutation was not found in 50 Saudi Arabian or 100 European samples.
In a French Canadian patient with juvenile-onset retinitis pigmentosa (RP94; see 604232), Wang et al. (2009) identified homozygosity for a 1-bp deletion (1546delA) in exon 12 of the SPATA7 gene, predicted to cause a frameshift and premature termination of the protein. The mutation was not found in 50 Saudi Arabian or 100 European samples.
In 2 brothers with childhood-onset retinal dystrophy (see 604232), offspring of nonconsanguineous British Caucasian parents, Mackay et al. (2011) identified compound heterozygous mutations in the SPATA7 gene: a 4-bp deletion (265_268delCTCA) in exon 5, resulting in a frameshift (Leu89LysfsTer3), and a 3-bp deletion (1227_1229delCAC; 609868.0006) in exon 12, resulting in deletion of a histidine at position 410 (H410del). The exon 5 deletion was inherited from the mother and the exon 12 deletion from the father. One of the brothers had clinical features consistent with LCA, having severe visual loss from early infancy, pendular nystagmus, and sluggish pupillary responses. His brother had a milder phenotype with onset of nystagmus at 8 weeks of age. He was able to fix and follow at this age. When older, he was noted to have severe nyctalopia and constricted visual fields. These symptoms deteriorated significantly from 14 years of age.
For discussion of the 3-bp deletion in the SPATA7 gene (1227_1229delCAC) that was found in compound heterozygous state in 2 brothers with childhood-onset retinal dystrophy (see 604232) by Mackay et al. (2011), see 609868.0005.
Leber Congenital Amaurosis 3
In 3 consanguineous families, 2 of Pakistani and 1 of Bangladeshi origin, with Leber congenital amaurosis-3 (LCA3; 604232), Mackay et al. (2011) identified homozygosity for a 253C-T transition in exon 5 of the SPATA7 gene, resulting in an arg85-to-ter (R85X) substitution.
Retinitis Pigmentosa 94, Variable Age at Onset
In 2 Spanish sibs from a consanguineous family with typical late-onset RP (RP94; see 604232), Avila-Fernandez et al. (2011) identified homozygosity for the R85X mutation in the SPATA7 gene. The authors suggested that the phenotypic variability might be explained by modifier alleles contributing to penetrance and expressivity, or intronic variants influencing severity.
In a 21-year-old Hispanic man with retinal degeneration that had progressed over 12 years from a cone-rod dystrophy phenotype to a late-stage RP phenotype (RP94; see 604232), Matsui et al. (2016) screened 163 retinal disease-associated genes and identified homozygosity for a 1-bp deletion (c.1373del) in the SPATA7 gene, causing a frameshift (Val458fs). His unaffected parents were heterozygous for the deletion.
In a 63-year-old man who had retinitis pigmentosa (RP94; see 604232) associated with prominent atrophy of the retinal pigment epithelium and choroidal sclerosis, Sengillo et al. (2018) identified compound heterozygosity for mutations in the SPATA7 gene: a c.1100A-G transition in exon 10 of the SPATA7 gene, resulting in a tyr367-to-cys (Y367C) substitution, and 2-bp deletion (c.1102_1103delCT; 609868.0010) in exon 10, causing a frameshift predicted to result in a premature termination codon (Leu368GlufsTer4). An unaffected family member was heterozygous for 1 of the variants, both of which were present at very low minor allele frequency (0.00003) in the gnomAD database.
For discussion of the 2-bp deletion (c.1102_1103delCT) in exon 10 of the SPATA7 gene, causing a frameshift predicted to result in a premature termination codon (Leu368GlufsTer4), that was found in compound heterozygous state in a 63-year-old man who had retinitis pigmentosa (RP94; see 604232) associated with prominent atrophy of the retinal pigment epithelium and choroidal sclerosis by Sengillo et al. (2018), see 609868.0009.
In a German brother and sister with retinal degeneration, diagnosed with rod-cone and cone-rod dystrophy, respectively, Feldhaus et al. (2018) analyzed genomic DNA using a panel of 286 retinal disease-associated genes, and identified homozygosity for a missense mutation in the SPATA7 gene (I371T; 609868.0011). The variant, which was found at low minor allele frequency (0.0003249) in the ExAC database, was present in heterozygosity in their 85-year-old mother, who had normal age-related findings on all tests; DNA was unavailable from the father.
Avila-Fernandez, A., Corton, M., Lopez-Molina, M. I., Martin-Garrido, E., Cantalapiedra, D., Fernandez-Sanchez, R., Blanco-Kelly, F., Riveiro-Alvarez, R., Tatu, S. D., Trujillo-Tiebas, M. J., Garcia-Sandoval, B., Ayuso, C., Cremers, F. P. M. Late onset retinitis pigmentosa. Ophthalmology 118: 2523-2524, 2011. [PubMed: 22136677] [Full Text: https://doi.org/10.1016/j.ophtha.2011.07.030]
Eblimit, A., Agrawal, S. A., Thomas, K., Anastassov, I. A., Abulikemu, T., Moayedi, Y., Mardon, G., Chen, R. Conditional loss of Spata7 in photoreceptors causes progressive retinal degeneration in mice. Exp. Eye Res. 166: 120-130, 2018. Note: Erratum: Exp Eye Res. 171: 119, 2018. [PubMed: 29100828] [Full Text: https://doi.org/10.1016/j.exer.2017.10.015]
Eblimit, A., Nguyen, T.-M. T., Chen, Y., Esteve-Rudd, J., Zhong, H., Letteboer, S., Van Reeuwijk, J., Simons, D. L., Ding, Q., Wu, K. M., Li, Y., Van Beersum, S., and 10 others. Spata7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina. Hum. Molec. Genet. 24: 1584-601, 2015. [PubMed: 25398945] [Full Text: https://doi.org/10.1093/hmg/ddu573]
Feldhaus, B., Kohl, S., Hortnagel, K., Weisschuh, N., Zobor, D. Novel homozygous mutation in the SPATA7 gene causes autosomal recessive retinal degeneration in a consanguineous German family. Ophthalmic Genet. 39: 131-134, 2018. [PubMed: 28481129] [Full Text: https://doi.org/10.1080/13816810.2017.1318925]
Li, Y., Wang, H., Peng, J., Gibbs, R. A., Lewis, R. A., Lupski, J. R., Mardon, G., Chen, R. Mutation survey of known LCA genes and loci in the Saudi Arabian population. Invest. Ophthal. Vis. Sci. 50: 1336-1343, 2009. [PubMed: 18936139] [Full Text: https://doi.org/10.1167/iovs.08-2589]
Mackay, D. S., Ocaka, L. A., Borman, A. D., Sergouniotis, P. I., Henderson, R. H., Moradi, P., Robson, A. G., Thompson, D. A., Webster, A. R., Moore, A. T. Screening of SPATA7 in patients with Leber congenital amaurosis and severe childhood-onset retinal dystrophy reveals disease-causing mutations. Invest. Ophthal. Vis. Sci. 52: 3032-3038, 2011. [PubMed: 21310915] [Full Text: https://doi.org/10.1167/iovs.10-7025]
Matsui, R., McGuigan, D. B., III, Gruzensky, M. L., Aleman, T. S., Schwartz, S. B., Sumaroka, A., Koenekoop, R. K., Cideciyan, A. V., Jacobson, S. G. SPATA7: evolving phenotype from cone-rod dystrophy to retinitis pigmentosa. Ophthalmic Genet. 37: 333-338, 2016. [PubMed: 26854980] [Full Text: https://doi.org/10.3109/13816810.2015.1130154]
Sengillo, J. D., Lee, W., Bilancia, C. G., Jobanputra, V., Tsang, S. H. Phenotypic expansion and progression of SPATA7-associated retinitis pigmentosa. Doc. Ophthal. 136: 125-133, 2018. [PubMed: 29411205] [Full Text: https://doi.org/10.1007/s10633-018-9626-1]
Wang, H., den Hollander, A. I., Moayedi, Y., Abulimiti, A., Li, Y., Collin, R. W. J., Hoyng, C. B., Lopez, I., Abboud, E. B., Al-Rajhi, A. A., Bray, M., Lewis, R. A., Lupski, J. R., Mardon, G., Koenekoop, R. K., Chen, R. Mutations in SPATA7 cause Leber congenital amaurosis and juvenile retinitis pigmentosa. Am. J. Hum. Genet. 84: 380-387, 2009. Note: Erratum: Am. J. Hum. Genet. 86: 293 only, 2010. [PubMed: 19268277] [Full Text: https://doi.org/10.1016/j.ajhg.2009.02.005]
Zhang, X. Liu, H., Zhang, Y., Qiao, Y., Miao, S., Wang, L., Zhang, J., Zong, S., Koide, S. S. A novel gene, RSD-3/HSD-3.1, encodes a meiotic-related protein expressed in rat and human testis. J. Molec. Med. 81: 380-387, 2003. [PubMed: 12736779] [Full Text: https://doi.org/10.1007/s00109-003-0434-y]