Novel mutations in the TULP1 and CNGB1 genes in a family affected with early onset severe retinal dystrophy_Chinese Journal of Ocular Fundus Diseases

Authors：

Wei Yuanmeng , Li Miao , Peng Haiying ,  Zhou Zhongqiang , Tang He , Shi Pingling , Liang Yingjuan , Tian Meizhi

Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou 450003, China;
Tian Meizhi is now working at Luyi County Eye Hospital, Zhoukou 477200, China;

Corresponding author：

Zhou Zhongqiang, Email: zhouzhongqiang110@163.com

Keywords：

Retinal dystrophy; Gene; Mutation; TULP1 gene; CNGB1 gene

DOI：

10.3760/cma.j.cn511434-20200427-00182

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Objective To identify the pathogenic gene mutations in a family with early onset severe retinal dystrophy (EOSRD).Methods A retrospective clinical study. One patient and three family members from a Han of EOSRD who were diagnosed at Henan Eye Hospital in August 2018 were included in the study. After the detailed history of the patients was collected, all participants underwent best corrected visual acuity (BCVA), slit-lamp, fundus biomicroscopy with the slit lamp, untra-widefield fundus color photography, spectral-domain optical coherence tomography (SD-OCT) and full-field electroretinography (ff-ERG). The subject’s peripheral venous blood of 5 ml was collected and the whole genome DNA was extracted. A genetic eye disease capture chip containing 441 disease-causing genes was used for targeted capture and enrichment of high-throughput sequencing, and Sanger sequencing was performed for the clear pathogenic mutation sites; the analysis software was used for bioinformatics analysis of the mutation sites.Results A 6-year-old female proband developed poor night vision in both eyes after 1 year old. The BCVA of both eyes were 0.1. The color of the optic disc was slightly lighter; the diameter of the retinal vessels was slightly reduced, and extensive pigment changes can be seen in the retina outside the vascular arch. SD-OCT examination showed that the outer membrane, ellipsoid zone and chimera zone in the central fovea of both eyes were unclear and intermittent. The visual area outside the fovea was neuroepithelial outer plexiform layer, outer nuclear layer, outer membrane, ellipsoid zone. The chimera zone gradually disappeared, and the thickness of the pigment epithelial layer was not uniform. In ff-ERG examination, the functions of the binocular cone and rod system were severely decreased. The results of genetic testing showed that there were c.921C>A homozygous mutations in the Tubby-like protein (TULP1) gene of the proband, and c.3121C>T and c.3488G>A compound heterozygous mutations in the cyclic nucleotide gated channel beta 1 (CNGB1) gene. Amino acid conservation analysis results showed that the above three mutation sites were highly conserved in multiple species; bioinformatics analysis results showed that TULP1 gene c.921C>A (p.Cys307*) had translation termination in the protein conserved region, CNGB1 gene c.3121C>T (p.Arg1041Trp) and c.3488G>A (p.Gly1163Glu) had amino acid polarity changes in the protein conserved region, which led to major changes in the protein spatial structure.Conclusion TULP1 gene c.921C>A homozygous mutation, CNGB1 gene c.3121C>T and c.3488G>A compound heterozygous mutation are the mutation sites of this EOSRD family.

Citation： Wei Yuanmeng, Li Miao, Peng Haiying, Zhou Zhongqiang, Tang He, Shi Pingling, Liang Yingjuan, Tian Meizhi. Novel mutations in the TULP1 and CNGB1 genes in a family affected with early onset severe retinal dystrophy. Chinese Journal of Ocular Fundus Diseases, 2021, 37(1): 47-53. doi: 10.3760/cma.j.cn511434-20200427-00182 Copy

1.	Kumaran N, Moore AT, Weleber RG, et al. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions[J]. Br J Ophthalmol, 2017, 101(9): 1147-1154. DOI: 10.1136/bjophthalmol-2016-309975.
2.	Xu K, Xie Y, Sun T, et al. Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy[J]. Br J Ophthalmol, 2020, 104(7): 932-937. DOI: 10.1136/bjophthalmol-2019-314281.
3.	唐贺, 彭海鹰, 史平玲, 等. RPGRIP1基因新突变致Leber先天性黑矇一家系[J]. 中华眼底病杂志, 2020, 36(3): 196-199. DOI: 10.3760/cma.j.cn511434-20191008-00315.Tang H, Peng HY, Shi PL, et al. Novel mutations of RPGRIP1 gene in a family with Leber congenital amaurosis[J]. Chin J Ocul Fundus Dis, 2020, 36(3): 196-199. DOI: 10.3760/cma.j.cn511434-20191008-00315.
4.	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.
5.	Mukhopadhyay S, Jackson PK. The tubby family proteins[J/OL]. Genome Biol, 2011, 12(6): 225[2011-06-28]. https://pubmed.ncbi.nlm.nih.gov/21722349/. DOI: 10.1186/gb-2011-12-6-225.
6.	Grossman GH, Pauer GJ, Narendra U, et al. Early synaptic defects in tulp1^-/- mice[J]. Invest Ophthalmol Vis Sci, 2009, 50(7): 3074-3083. DOI: 10.1167/iovs.08-3190.
7.	Hagstrom SA, Adamian M, Scimeca M, et al. A role for the Tubby-like protein 1 in rhodopsin transport[J]. Invest Ophthalmol Vis Sci, 2001, 42(9): 1955-1962.
8.	Hagstrom SA, Watson RF, Pauer GJ, et al. TULP1 is involved in specific photoreceptor protein transport pathways[J]. Adv Exp Med Biol, 2012, 723: 783-789. DOI: 10.1007/978-1-4614-0631-0_100.
9.	Grossman GH, Watson RF, Pauer GJ, et al. Immunocytochemical evidence of Tulp1-dependent outer segment protein transport pathways in photoreceptor cells[J]. Exp Eye Res, 2011, 93(5): 658-668. DOI: 10.1016/j.exer.2011.08.005.
10.	Wahl S, Magupalli VG, Dembla M, et al. The disease protein TULP1 is essential for periactive zone endocytosis in photoreceptor ribbon synapses[J]. J Neurosci, 2016, 36(8): 2473-2493. DOI: 10.1523/JNEUROSCI.2275-15.2016.
11.	Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis[J]. Hum Mutat, 2004, 23(4): 306-317. DOI: 10.1002/humu.20010.
12.	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.
13.	den Hollander AI, Lopez I, Yzer S, et al. Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays[J]. Invest Ophthalmol Vis Sci, 2007, 48(12): 5690-5698. DOI: 10.1167/iovs.07-0610.
14.	den Hollander AI, Roepman R, Koenekoop RK, et al. Leber congenital amaurosis: genes, proteins and disease mechanisms[J]. Prog Ret Eye Res, 2008, 27(4): 391-419. DOI: 10.1016/j.preteyeres.2008.05.003.
15.	Kondo H, Qin M, Mizota A, et al. A homozygosity-based search for mutations in patients with autosomal recessive retinitis pigmentosa, using microsatellite markers[J]. Invest Ophthalmol Vis Sci, 2004, 45(12): 4433-4439. DOI: 10.1167/iovs.04-0544.
16.	Colville CA, Molday RS. Primary structure and expression of the human beta-subunit and related proteins of the rod photoreceptor cGMP-gated channel[J]. J Biol Chem, 1996, 271(51): 32968-32974. DOI: 10.1074/jbc.271.51.32968.
17.	Korenbrot JI. Speed, sensitivity, and stability of the light response in rod and cone photoreceptors: facts and models[J]. Prog Retin Eye Res, 2012, 31(5): 442-466. DOI: 10.1016/j.preteyeres.2012.05.002.
18.	Pentia DC, Hosier S, Cote RH. The glutamic acid-rich protein-2(GARP2) is a high affinity rod photoreceptor phosphodiesterase (PDE6)-binding protein that modulates its catalytic properties[J]. J Biol Chem, 2006, 281(9): 5500-5505. DOI: 10.1074/jbc.M507488200.
19.	Poetsch A, Molday LL, Molday RS. The cGMP-gated channel and related glutamic acid-rich proteins interact with peripherin-2 at the rim region of rod photoreceptor disc membranes[J]. J Biol Chem, 2001, 276(51): 48009-48016. DOI: 10.1074/jbc.M108941200.
20.	Bareil C, Hamel CP, Delague V, et al. Segregation of a mutation in CNGB1 encoding the beta-subunit of the rod cGMP-gated channel in a family with autosomal recessive retinitis pigmentosa[J]. Hum Genet, 2001, 108(4): 328-334. DOI: 10.1007/s004390100496.
21.	Maranhao B, Biswas P, Gottsch AD, et al. Investigating the molecular basis of retinal degeneration in a familial cohort of Pakistani descent by exome sequencing[J/OL]. PLoS One, 2015, 10(9): e0136561[2015-09-09]. https://pubmed.ncbi.nlm.nih.gov/26352687/. DOI: 10.1371/journal.pone.0136561.

1. Kumaran N, Moore AT, Weleber RG, et al. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions[J]. Br J Ophthalmol, 2017, 101(9): 1147-1154. DOI: 10.1136/bjophthalmol-2016-309975.
2. Xu K, Xie Y, Sun T, et al. Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy[J]. Br J Ophthalmol, 2020, 104(7): 932-937. DOI: 10.1136/bjophthalmol-2019-314281.
3. 唐贺, 彭海鹰, 史平玲, 等. RPGRIP1基因新突变致Leber先天性黑矇一家系[J]. 中华眼底病杂志, 2020, 36(3): 196-199. DOI: 10.3760/cma.j.cn511434-20191008-00315.Tang H, Peng HY, Shi PL, et al. Novel mutations of RPGRIP1 gene in a family with Leber congenital amaurosis[J]. Chin J Ocul Fundus Dis, 2020, 36(3): 196-199. DOI: 10.3760/cma.j.cn511434-20191008-00315.
4. 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.
5. Mukhopadhyay S, Jackson PK. The tubby family proteins[J/OL]. Genome Biol, 2011, 12(6): 225[2011-06-28]. https://pubmed.ncbi.nlm.nih.gov/21722349/. DOI: 10.1186/gb-2011-12-6-225.
6. Grossman GH, Pauer GJ, Narendra U, et al. Early synaptic defects in tulp1^-/- mice[J]. Invest Ophthalmol Vis Sci, 2009, 50(7): 3074-3083. DOI: 10.1167/iovs.08-3190.
7. Hagstrom SA, Adamian M, Scimeca M, et al. A role for the Tubby-like protein 1 in rhodopsin transport[J]. Invest Ophthalmol Vis Sci, 2001, 42(9): 1955-1962.
8. Hagstrom SA, Watson RF, Pauer GJ, et al. TULP1 is involved in specific photoreceptor protein transport pathways[J]. Adv Exp Med Biol, 2012, 723: 783-789. DOI: 10.1007/978-1-4614-0631-0_100.
9. Grossman GH, Watson RF, Pauer GJ, et al. Immunocytochemical evidence of Tulp1-dependent outer segment protein transport pathways in photoreceptor cells[J]. Exp Eye Res, 2011, 93(5): 658-668. DOI: 10.1016/j.exer.2011.08.005.
10. Wahl S, Magupalli VG, Dembla M, et al. The disease protein TULP1 is essential for periactive zone endocytosis in photoreceptor ribbon synapses[J]. J Neurosci, 2016, 36(8): 2473-2493. DOI: 10.1523/JNEUROSCI.2275-15.2016.
11. Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis[J]. Hum Mutat, 2004, 23(4): 306-317. DOI: 10.1002/humu.20010.
12. 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.
13. den Hollander AI, Lopez I, Yzer S, et al. Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays[J]. Invest Ophthalmol Vis Sci, 2007, 48(12): 5690-5698. DOI: 10.1167/iovs.07-0610.
14. den Hollander AI, Roepman R, Koenekoop RK, et al. Leber congenital amaurosis: genes, proteins and disease mechanisms[J]. Prog Ret Eye Res, 2008, 27(4): 391-419. DOI: 10.1016/j.preteyeres.2008.05.003.
15. Kondo H, Qin M, Mizota A, et al. A homozygosity-based search for mutations in patients with autosomal recessive retinitis pigmentosa, using microsatellite markers[J]. Invest Ophthalmol Vis Sci, 2004, 45(12): 4433-4439. DOI: 10.1167/iovs.04-0544.
16. Colville CA, Molday RS. Primary structure and expression of the human beta-subunit and related proteins of the rod photoreceptor cGMP-gated channel[J]. J Biol Chem, 1996, 271(51): 32968-32974. DOI: 10.1074/jbc.271.51.32968.
17. Korenbrot JI. Speed, sensitivity, and stability of the light response in rod and cone photoreceptors: facts and models[J]. Prog Retin Eye Res, 2012, 31(5): 442-466. DOI: 10.1016/j.preteyeres.2012.05.002.
18. Pentia DC, Hosier S, Cote RH. The glutamic acid-rich protein-2(GARP2) is a high affinity rod photoreceptor phosphodiesterase (PDE6)-binding protein that modulates its catalytic properties[J]. J Biol Chem, 2006, 281(9): 5500-5505. DOI: 10.1074/jbc.M507488200.
19. Poetsch A, Molday LL, Molday RS. The cGMP-gated channel and related glutamic acid-rich proteins interact with peripherin-2 at the rim region of rod photoreceptor disc membranes[J]. J Biol Chem, 2001, 276(51): 48009-48016. DOI: 10.1074/jbc.M108941200.
20. Bareil C, Hamel CP, Delague V, et al. Segregation of a mutation in CNGB1 encoding the beta-subunit of the rod cGMP-gated channel in a family with autosomal recessive retinitis pigmentosa[J]. Hum Genet, 2001, 108(4): 328-334. DOI: 10.1007/s004390100496.
21. Maranhao B, Biswas P, Gottsch AD, et al. Investigating the molecular basis of retinal degeneration in a familial cohort of Pakistani descent by exome sequencing[J/OL]. PLoS One, 2015, 10(9): e0136561[2015-09-09]. https://pubmed.ncbi.nlm.nih.gov/26352687/. DOI: 10.1371/journal.pone.0136561.

Chinese Journal of Ocular Fundus Diseases

Novel mutations in the TULP1 and CNGB1 genes in a family affected with early onset severe retinal dystrophy

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