Genotypic and phenotypic analysis in a family affected with sector retinitis pigmentosa and macular dystrophy caused by Spermatogenesis-associated protein 7 gene_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhou Lingling , Tong Yan , Yan Jiangbo ,  Shen Yin

Eye Center, Renmin Hospital of Wuhan University, Wuhan 430060, China;

Corresponding author：

Shen Yin, Email: yinshen@whu.edu.cn

Keywords：

Retinitis pigmentosa; Macular dystrophy; Genes; Mutation; SPATA7 gene

DOI：

10.3760/cma.j.cn511434-20211206-00683

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To analyze the pathogenic gene and clinical phenotypes of a family affected with rare sector retinitis pigmentosa (sector RP). Methods A retrospective clinical study. A patient with sector RP diagnosed in Renmin Hospital of Wuhan University and his parents were included in the study. Detailed medical history was collected; best corrected visual acuity (BCVA), fundus color photography, autofluorescence (AF), visual field, optical coherence tomography (OCT), electroretinogram, fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA) examination were performed. The peripheral venous blood of the patient and his parents were collected, and DNA was extracted. A whole exon sequencing was used for the proband. The mutations were verified by targeted Sanger sequencing and quantitative polymerase chain reaction. Bioinformatics analysis and cosegregation analysis were performed. Results The proband, a 17-year-old male, had presented with gradually decreased vision in the past 2 years with BCVA of 0.4 in both eyes. Retinal vessels attenuation and macular dystrophy without obvious pigmentation on the fundus were observed. AF showed, in bilateral eyes, a symmetrical hypo-autofluorescent region only in the inferonasal quadrant and “petal-like” hyper-AF macula. The visual field examination showed defects in the superotemporal quadrant corresponding to the affected retina. OCT showed loss of the photoreceptor layer except for the foveal region. Electroretinogram examination presented reduced scotopic wave peaks and extinct photopic response. FFA and ICGA showed the atrophy retinal pigment epithelium around the optic disk and in the inferior retina. The clinical phenotypes of the parents were normal. The whole exon sequencing identified one mutation in SPATA7 gene, c.1112T>C (p.Ile371Thr) in exon10 and a copy number variation in trans. The missense mutation resulted in the change of isoleucine to threonine at amino acid 371 in the encoded SPATA7 protein, and the mother carried this heterozygous mutation c.1112T>C. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG) criteria and guidelines for classification of genetic variants, the missense mutation was classified as the uncertain significance. The CNV, originating from his father, contributed to the loss of exon10 and was confirmed as the likely pathogenic variant. Conclusions The macula can be involved in sector RP, leading to the macular dystrophy. The missense variant in SPATA7 gene, c.1112T>C (p.Ile371Thr), might be a pathogenic mutation site in this pedigree.

Citation： Zhou Lingling, Tong Yan, Yan Jiangbo, Shen Yin. Genotypic and phenotypic analysis in a family affected with sector retinitis pigmentosa and macular dystrophy caused by Spermatogenesis-associated protein 7 gene. Chinese Journal of Ocular Fundus Diseases, 2022, 38(8): 643-649. doi: 10.3760/cma.j.cn511434-20211206-00683 Copy

1.	Verbakel SK, van Huet RAC, Boon CJF, et al. Non-syndromic retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 66: 157-186. DOI: 10.1016/j.preteyeres.2018.03.005.
2.	Napier ML, Durga D, Wolsley CJ, et al. Mutational analysis of the rhodopsin gene in sector retinitis pigmentosa[J]. Ophthalmic Genet, 2015, 36(3): 239-243. DOI: 10.3109/13816810.2014.958862.
3.	Stone EM, Kimura AE, Nichols BE, et al. Regional distribution of retinal degeneration in patients with the proline to histidine mutation in codon 23 of the rhodopsin gene[J]. Ophthalmology, 1991, 98(12): 1806-1813. DOI: 10.1016/s0161-6420(91)32046-3.
4.	Van Woerkom C, Ferrucci S. Sector retinitis pigmentosa[J]. Optometry, 2005, 76(5): 309-317. DOI: 10.1016/s1529-1839(05)70314-6.
5.	Grover S, Fishman GA, Anderson RJ, et al. Visual acuity impairment in patients with retinitis pigmentosa at age 45 years or older[J]. Ophthalmology, 1999, 106(9): 1780-1785. DOI: 10.1016/S0161-6420(99)90342-1.
6.	Georgiou M, Grewal PS, Narayan A, et al. Sector retinitis pigmentosa: extending the molecular genetics basis and elucidating the natural history[J]. Am J Ophthalmol, 2021, 221: 299-310. DOI: 10.1016/j.ajo.2020.08.004.
7.	Perrault I, Hanein S, Gerard X, et al. Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype[J/OL]. Hum Mutat, 2010, 31(3): e1241-1250[2010-03-01]. https://pubmed.ncbi.nlm.nih.gov/20104588/. DOI: 10.1002/humu.21203.
8.	Wang H, den Hollander AI, Moayedi Y, et al. Mutations in SPATA7 cause Leber congenital amaurosis and juvenile retinitis pigmentosa[J]. Am J Hum Genet, 2009, 84(3): 380-387. DOI: 10.1016/j.ajhg.2009.02.005.
9.	Feldhaus B, Kohl S, Hörtnagel K, et al. Novel homozygous mutation in the SPATA7 gene causes autosomal recessive retinal degeneration in a consanguineous German family[J]. Ophthalmic Genet, 2018, 39(1): 131-134. DOI: 10.1080/13816810.2017.1318925.
10.	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
11.	Eisenberger T, Neuhaus C, Khan AO, et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies[J/OL]. PLoS One, 2013, 8(11): e78496[2013-11-12]. https://pubmed.ncbi.nlm.nih.gov/24265693/. DOI: 10.1371/journal.pone.0078496.
12.	Takahashi VKL, Takiuti JT, Jauregui R, et al. Rates of bone spicule pigment appearance in patients with retinitis pigmentosa sine pigmento[J]. Am J Ophthalmol, 2018, 195: 176-180. DOI: 10.1016/j.ajo.2018.07.036.
13.	Schwartz L, Boëlle PY, D' Hermies F, et al. Blue light dose distribution and retinitis pigmentosa visual field defects: an hypothesis[J]. Med Hypotheses, 2003, 60(5): 644-649. DOI: 10.1016/s0306-9877(02)00391-2.
14.	McDonald HR, Schatz H, Johnson RN. Ocular phototoxicitiy[J]. Curr Opin Ophthalmol, 1990, 1(3): 280-284. DOI: 10.1097/00055735-199006000-00012.
15.	Jacobson SG, Acland GM, Aguirre GD, et al. Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection[J]. Mol Ther, 2006, 13(6): 1074-1084. DOI: 10.1016/j.ymthe.2006.03.005.
16.	Rózanowska M, Sarna T. Light-induced damage to the retina: role of rhodopsin chromophore revisited[J]. Photochem Photobiol, 2005, 81(6): 1305-1330. DOI: 10.1562/2004-11-13-ir-371.
17.	Naash ML, Peachey NS, Li ZY, et al. Light-induced acceleration of photoreceptor degeneration in transgenic mice expressing mutant rhodopsin[J]. Invest Ophthalmol Vis Sci, 1996, 37(5): 775-782.
18.	Gass JD, Agarwal A, Scott IU. Acute zonal occult outer retinopathy: a long-term follow-up study[J]. Am J Ophthalmol, 2002, 134(3): 329-339. DOI: 10.1016/s0002-9394(02)01640-9.
19.	Eblimit A, Nguyen TM, Chen Y, et al. SPATA7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina[J]. Hum Mol Genet, 2015, 24(6): 1584-1601. DOI: 10.1093/hmg/ddu573.
20.	Dharmat R, Eblimit A, Robichaux MA, et al. SPATA7 maintains a novel photoreceptor-specific zone in the distal connecting cilium[J]. J Cell Biol, 2018, 217(8): 2851-2865. DOI: 10.1083/jcb.201712117.
21.	Wang X, Wang H, Sun V, et al. Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing[J]. J Med Genet, 2013, 50(10): 674-688. DOI: 10.1136/jmedgenet-2013-101558.
22.	Stockton DW, Lewis RA, Abboud EB, et al. A novel locus for Leber congenital amaurosis on chromosome 14q24[J]. Hum Genet, 1998, 103(3): 328-333. DOI: 10.1007/s004390050825.
23.	Xiao X, Sun W, Li S, et al. Spectrum, frequency, and genotype-phenotype of mutations in SPATA7[J]. Mol Vis, 2019, 25: 821-833.
24.	Coussa RG, Basali D, Maeda A, et al. Sector retinitis pigmentosa: report of ten cases and a review of the literature[J]. Mol Vis, 2019, 25: 869-889.
25.	Heckenlively JR, Rodriguez JA, Daiger SP. Autosomal dominant sectoral retinitis pigmentosa. Two families with transversion mutation in codon 23 of rhodopsin[J]. Arch Ophthalmol, 1991, 109(1): 84-91. DOI: 10.1001/archopht.1991.01080010086038.
26.	Saihan Z, Stabej Ple Q, Robson AG, et al. Mutations in the USH1C gene associated with sector retinitis pigmentosa and hearing loss[J]. Retina, 2011, 31(8): 1708-1716. DOI: 10.1097/IAE.0b013e31820d3fd1.
27.	Branson SV, McClintic JI, Stamper TH, et al. Sector retinitis pigmentosa associated with novel compound heterozygous mutations of CDH23[J]. Ophthalmic Surg Lasers Imaging Retina, 2016, 47(2): 183-186. DOI: 10.3928/23258160-20160126-14.
28.	Marques JP, Porto FBO, Carvalho AL, et al. Eye-associated sector retinitis pigmentosa[J]. Graefe's Arch Clin Exp Ophthalmol, 2022, 260(4): 1405-1413. DOI: 10.1007/s00417-021-05411-w.
29.	Nakamachi Y, Nakamura M, Fujii S, et al. Oguchi disease with sectoral retinitis pigmentosa harboring adenine deletion at position 1147 in the arrestin gene[J]. Am J Ophthalmol, 1998, 125(2): 249-251. DOI: 10.1016/s0002-9394(99)80100-7.
30.	Pappalardo J, Heath Jeffery RC, Thompson JA, et al. Progressive sector retinitis pigmentosa due to c. 440G>T mutation in SAG in an Australian family[J]. Ophthalmic Genet, 2021, 42(1): 62-70. DOI: 10.1080/13816810.2020.1832533.
31.	Sato M, Oshika T, Kaji Y, et al. A novel homozygous Gly107Arg mutation in the RDH5 gene in a Japanese patient with fundus albipunctatus with sectorial retinitis pigmentosa[J]. Ophthalmic Res, 2004, 36(1): 43-50. DOI: 10.1159/000076109.
32.	Nguyen XT, Talib M, van Schooneveld MJ, et al. RPGR-associated dystrophies: clinical, genetic, and histopathological features[J]. Int J Mol Sci, 2020, 21(3): 835. DOI: 10.3390/ijms21030835.
33.	Zhong H, Eblimit A, Moayedi Y, et al. AAV8 (Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa[J]. Gene Ther, 2015, 22(8): 619-627. DOI: 10.1038/gt.2015.42.

1. Verbakel SK, van Huet RAC, Boon CJF, et al. Non-syndromic retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 66: 157-186. DOI: 10.1016/j.preteyeres.2018.03.005.
2. Napier ML, Durga D, Wolsley CJ, et al. Mutational analysis of the rhodopsin gene in sector retinitis pigmentosa[J]. Ophthalmic Genet, 2015, 36(3): 239-243. DOI: 10.3109/13816810.2014.958862.
3. Stone EM, Kimura AE, Nichols BE, et al. Regional distribution of retinal degeneration in patients with the proline to histidine mutation in codon 23 of the rhodopsin gene[J]. Ophthalmology, 1991, 98(12): 1806-1813. DOI: 10.1016/s0161-6420(91)32046-3.
4. Van Woerkom C, Ferrucci S. Sector retinitis pigmentosa[J]. Optometry, 2005, 76(5): 309-317. DOI: 10.1016/s1529-1839(05)70314-6.
5. Grover S, Fishman GA, Anderson RJ, et al. Visual acuity impairment in patients with retinitis pigmentosa at age 45 years or older[J]. Ophthalmology, 1999, 106(9): 1780-1785. DOI: 10.1016/S0161-6420(99)90342-1.
6. Georgiou M, Grewal PS, Narayan A, et al. Sector retinitis pigmentosa: extending the molecular genetics basis and elucidating the natural history[J]. Am J Ophthalmol, 2021, 221: 299-310. DOI: 10.1016/j.ajo.2020.08.004.
7. Perrault I, Hanein S, Gerard X, et al. Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype[J/OL]. Hum Mutat, 2010, 31(3): e1241-1250[2010-03-01]. https://pubmed.ncbi.nlm.nih.gov/20104588/. DOI: 10.1002/humu.21203.
8. Wang H, den Hollander AI, Moayedi Y, et al. Mutations in SPATA7 cause Leber congenital amaurosis and juvenile retinitis pigmentosa[J]. Am J Hum Genet, 2009, 84(3): 380-387. DOI: 10.1016/j.ajhg.2009.02.005.
9. Feldhaus B, Kohl S, Hörtnagel K, et al. Novel homozygous mutation in the SPATA7 gene causes autosomal recessive retinal degeneration in a consanguineous German family[J]. Ophthalmic Genet, 2018, 39(1): 131-134. DOI: 10.1080/13816810.2017.1318925.
10. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
11. Eisenberger T, Neuhaus C, Khan AO, et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies[J/OL]. PLoS One, 2013, 8(11): e78496[2013-11-12]. https://pubmed.ncbi.nlm.nih.gov/24265693/. DOI: 10.1371/journal.pone.0078496.
12. Takahashi VKL, Takiuti JT, Jauregui R, et al. Rates of bone spicule pigment appearance in patients with retinitis pigmentosa sine pigmento[J]. Am J Ophthalmol, 2018, 195: 176-180. DOI: 10.1016/j.ajo.2018.07.036.
13. Schwartz L, Boëlle PY, D' Hermies F, et al. Blue light dose distribution and retinitis pigmentosa visual field defects: an hypothesis[J]. Med Hypotheses, 2003, 60(5): 644-649. DOI: 10.1016/s0306-9877(02)00391-2.
14. McDonald HR, Schatz H, Johnson RN. Ocular phototoxicitiy[J]. Curr Opin Ophthalmol, 1990, 1(3): 280-284. DOI: 10.1097/00055735-199006000-00012.
15. Jacobson SG, Acland GM, Aguirre GD, et al. Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection[J]. Mol Ther, 2006, 13(6): 1074-1084. DOI: 10.1016/j.ymthe.2006.03.005.
16. Rózanowska M, Sarna T. Light-induced damage to the retina: role of rhodopsin chromophore revisited[J]. Photochem Photobiol, 2005, 81(6): 1305-1330. DOI: 10.1562/2004-11-13-ir-371.
17. Naash ML, Peachey NS, Li ZY, et al. Light-induced acceleration of photoreceptor degeneration in transgenic mice expressing mutant rhodopsin[J]. Invest Ophthalmol Vis Sci, 1996, 37(5): 775-782.
18. Gass JD, Agarwal A, Scott IU. Acute zonal occult outer retinopathy: a long-term follow-up study[J]. Am J Ophthalmol, 2002, 134(3): 329-339. DOI: 10.1016/s0002-9394(02)01640-9.
19. Eblimit A, Nguyen TM, Chen Y, et al. SPATA7 is a retinal ciliopathy gene critical for correct RPGRIP1 localization and protein trafficking in the retina[J]. Hum Mol Genet, 2015, 24(6): 1584-1601. DOI: 10.1093/hmg/ddu573.
20. Dharmat R, Eblimit A, Robichaux MA, et al. SPATA7 maintains a novel photoreceptor-specific zone in the distal connecting cilium[J]. J Cell Biol, 2018, 217(8): 2851-2865. DOI: 10.1083/jcb.201712117.
21. Wang X, Wang H, Sun V, et al. Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing[J]. J Med Genet, 2013, 50(10): 674-688. DOI: 10.1136/jmedgenet-2013-101558.
22. Stockton DW, Lewis RA, Abboud EB, et al. A novel locus for Leber congenital amaurosis on chromosome 14q24[J]. Hum Genet, 1998, 103(3): 328-333. DOI: 10.1007/s004390050825.
23. Xiao X, Sun W, Li S, et al. Spectrum, frequency, and genotype-phenotype of mutations in SPATA7[J]. Mol Vis, 2019, 25: 821-833.
24. Coussa RG, Basali D, Maeda A, et al. Sector retinitis pigmentosa: report of ten cases and a review of the literature[J]. Mol Vis, 2019, 25: 869-889.
25. Heckenlively JR, Rodriguez JA, Daiger SP. Autosomal dominant sectoral retinitis pigmentosa. Two families with transversion mutation in codon 23 of rhodopsin[J]. Arch Ophthalmol, 1991, 109(1): 84-91. DOI: 10.1001/archopht.1991.01080010086038.
26. Saihan Z, Stabej Ple Q, Robson AG, et al. Mutations in the USH1C gene associated with sector retinitis pigmentosa and hearing loss[J]. Retina, 2011, 31(8): 1708-1716. DOI: 10.1097/IAE.0b013e31820d3fd1.
27. Branson SV, McClintic JI, Stamper TH, et al. Sector retinitis pigmentosa associated with novel compound heterozygous mutations of CDH23[J]. Ophthalmic Surg Lasers Imaging Retina, 2016, 47(2): 183-186. DOI: 10.3928/23258160-20160126-14.
28. Marques JP, Porto FBO, Carvalho AL, et al. Eye-associated sector retinitis pigmentosa[J]. Graefe's Arch Clin Exp Ophthalmol, 2022, 260(4): 1405-1413. DOI: 10.1007/s00417-021-05411-w.
29. Nakamachi Y, Nakamura M, Fujii S, et al. Oguchi disease with sectoral retinitis pigmentosa harboring adenine deletion at position 1147 in the arrestin gene[J]. Am J Ophthalmol, 1998, 125(2): 249-251. DOI: 10.1016/s0002-9394(99)80100-7.
30. Pappalardo J, Heath Jeffery RC, Thompson JA, et al. Progressive sector retinitis pigmentosa due to c. 440G>T mutation in SAG in an Australian family[J]. Ophthalmic Genet, 2021, 42(1): 62-70. DOI: 10.1080/13816810.2020.1832533.
31. Sato M, Oshika T, Kaji Y, et al. A novel homozygous Gly107Arg mutation in the RDH5 gene in a Japanese patient with fundus albipunctatus with sectorial retinitis pigmentosa[J]. Ophthalmic Res, 2004, 36(1): 43-50. DOI: 10.1159/000076109.
32. Nguyen XT, Talib M, van Schooneveld MJ, et al. RPGR-associated dystrophies: clinical, genetic, and histopathological features[J]. Int J Mol Sci, 2020, 21(3): 835. DOI: 10.3390/ijms21030835.
33. Zhong H, Eblimit A, Moayedi Y, et al. AAV8 (Y733F)-mediated gene therapy in a Spata7 knockout mouse model of Leber congenital amaurosis and retinitis pigmentosa[J]. Gene Ther, 2015, 22(8): 619-627. DOI: 10.1038/gt.2015.42.

Chinese Journal of Ocular Fundus Diseases

Genotypic and phenotypic analysis in a family affected with sector retinitis pigmentosa and macular dystrophy caused by Spermatogenesis-associated protein 7 gene

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content