Genetic analysis of the <i>CACNA1F</i> gene in a family affected with incomplete form Schubert-Bornschein type congenital stationary night blindness_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Guanfeng ¹ , Zhou Zhongqiang ² , Tang He ² , Wei Yuanmeng ² ,  Peng Haiying ² , Shi Pingling ² , Liang Yingjuan ² , Sun Xiantao ¹ , Lu Yuebing ¹

1. Department of Opthalmology, Henan Children's Hospital, Children's Hospital Affiliated of Zhengzhou University, Henan Provincial Key Laboratory of Children's Genetic and Metabolic Diseases, Zhengzhou 450018, China;
2. Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou 450003, China;

Corresponding author：

Peng Haiying, Email: angelphy@163.com

Keywords：

Night Blindness; Eye diseases, hereditary; CACNA1F gene mutation

DOI：

10.3760/cma.j.cn511434-20210930-00560

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To determine the pathogenic gene mutation in a family with incomplete congenital quiescent night blindness (CSNB) of Schubert-Bornschein type. Methods A retrospective clinical study. In February 2021, one patient and his parents and elder brother from a Han Chinese incomplete CSNB of Schubert-Bornschein type family diagnosed by clinical and genetic examination at Henan Provincial People's Hospital were included in the study. The patient’s medical history, family history were inquired; best corrected visual acuity (BCVA), color vision, fundus color photography, full-field electroretinogram (ERG), and frequency domain optical coherence tomography (OCT) were examined in detail. Five ml of the subject’s peripheral venous blood was collected and the whole genome DNA was extracted. The genomic DNA of the subject was library constructed, and all-exon probes were polymerized for capture. The suspected pathogenic mutation site was verified by Sanger, and the pathogenicity of the gene mutation site was determined by parallel bioinformatics analysis. Results The BCVA of both eyes of the proband (Ⅱ2) was 0.4; the color vision test could not recognize the red color. Fundus examination showed no obvious abnormalities. The retina thickness in the macular area of both eyes was slightly thinned. ERG examination of the whole field showed that the amplitude of ERG b wave was significantly reduced under the stimulation of binocular dark adaptation 3.0 and showed a negative waveform. The mother of the proband (Ⅰ2) had normal BCVA, color vision, fundus color photography, and frequency domain OCT examination. The full-field ERG examination showed that the amplitude of each eye reaction was slightly reduced, and the amplitude of the dark adaptation shock potential was significantly reduced. Genetic testing showed that the proband (Ⅱ2) had a c.1761dupC hemizygous mutation in exon 14 of the voltage-dependent calcium channel α1F subunit gene (CACNA1F gene). The results of protein sequence homology analysis showed that the site was highly conserved in multiple species; the results of bioinformatics analysis showed that the CACNA1F gene c.1761dupC (pY588fs) subsequently had a frameshift mutation and became a stop at position 10. Codons appear translational termination in the conserved regions of the protein. According to the standards and guidelines of the American College of Medical Genetics and Genomics, the mutation was judged to be a possible pathogenic variant. The mother of the proband (Ⅰ2) was a carrier of this site mutation. The clinical and genetic test results of the father and elder brother of the proband were not abnormal. Conclusion CACNA1F gene c.1761dupC is the pathogenic mutation site of the Schubert-Bornschein type incomplete CSNB family.

Citation： Li Guanfeng, Zhou Zhongqiang, Tang He, Wei Yuanmeng, Peng Haiying, Shi Pingling, Liang Yingjuan, Sun Xiantao, Lu Yuebing. Genetic analysis of the CACNA1F gene in a family affected with incomplete form Schubert-Bornschein type congenital stationary night blindness. Chinese Journal of Ocular Fundus Diseases, 2021, 37(11): 860-864. doi: 10.3760/cma.j.cn511434-20210930-00560 Copy

1.	苏钰, 文峰, 易长贤. 先天性静止性夜盲[M]//文峰, 易长贤. 临床眼底病·内科卷. 北京: 人民卫生出版社, 2015: 533-537.Su Y, Wen F, Yi CX. Congenital stationary night blindness[M]//Wen F, Yi CX. Clinical ophthalmic disease (internal medicine volume). Beijing: People's Medical Publishing House, 2015: 533-537.
2.	De Silva SR, Arno G, Robson AG, et al. The X-linked retinopathies: physiological insights, pathogenic mechanisms, phenotypic features and novel therapies[J/OL]. Prog Retin Eye Res, 2021, 82: 100898[2020-08-06]. https://pubmed.ncbi.nlm.nih.gov/32860923/. DOI: 10.1016/j.preteyeres.2020.100898.
3.	Zeitz C, Robson AG, Audo I. Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms[J]. Prog Retin Eye Res, 2015, 45: 58-110. DOI: 10.1016/j.preteyeres.2014.09.001.
4.	Almutairi F, Almeshari N, Ahmad K, et al. Congenital stationary night blindness: an update and review of the disease spectrum in Saudi Arabia[J]. Acta Ophthalmologica, 2021, 99(6): 581-591. DOI: 10.1111/aos.14693.
5.	Hove MN, Kilic-Biyik KZ, Trotter A, et al. Clinical characteristics, mutation spectrum, and prevalence of Åland eye disease/incomplete congenital stationary night blindness in Denmark[J]. Invest Ophthalmol Vis Sci, 2016, 57(15): 6861-6869. DOI: 10.1167/iovs.16-19445.
6.	Kim HM, Joo K, Han J, et al. Clinical and genetic characteristics of Korean congenital stationary night blindness patients[J]. Genes (Basel), 2021, 12(6): 789. DOI: 10.3390/genes12060789.
7.	Zeitz C, Michiels C, Neuillé M, et al. Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders[J]. Human Mutation, 2019, 40(6): 765-787. DOI: 10.1002/humu.23735.
8.	Mahmood U, Méjécase C, Ali SMA, et al. A novel splice-site variant in CACNA1F causes a phenotype synonymous with Åland island eye disease and incomplete congenital stationary night blindness[J]. Genes (Basel), 2021, 12(2): 171. DOI: 10.3390/genes12020171.
9.	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.
10.	RIGGS LA. Electroretinography in cases of night blindness[J]. Am J Ophthalmol, 1954, 38(1: 2): 70-78. DOI: 10.1016/0002-9394(54)90011-2.
11.	睢瑞芳, 李凤荣, 赵家良, 等. 完全型X连锁先天性静止性夜盲临床和基因研究[J]. 中华眼底病杂志, 2007, 23(3): 184-188. DOI: 10.3760/j.issn:1005-1015.2007.03.009.Sui RF, Li FR, Zhao JL, et al. Clinical and genetic study of complete X-linked congenital quiescent night blindness[J]. Chin J Ocul Fundus Dis, 2007, 23(3): 184-188. DOI: 10.3760/j.issn:1005-1015.2007.03.009.
12.	Matthews G, Fuchs P. The diverse roles of ribbon synapses in sensory neurotransmission[J]. Nat Rev Neurosci, 2010, 11(12): 812-822. DOI: 10.1038/nrn2924.
13.	Chang B, Heckenlively JR, Bayley PR, et al. The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses[J]. Vis Neurosci, 2006, 23(1): 11-24. DOI: 10.1017/S095252380623102X.
14.	Bech-Hansen NT, Naylor MJ, Maybaum TA, et al. Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness[J]. Nat Genet, 1998, 19(3): 264-267. DOI: 10.1038/947.
15.	Koschak A, Fernandez-Quintero ML, Heigl T, et al. Cav1.4 dysfunction and congenital stationary night blindness type 2[J]. Pflugers Arch, 2021, 473(9): 1437-1454. DOI: 10.1007/s00424-021-02570-x.
16.	Jia S, Muto A, Orisme W, et al. Zebrafish Cacna1fa is required for cone photoreceptor function and synaptic ribbon formation[J]. Hum Mol Genet, 2014, 23(11): 2981-2994. DOI: 10.1093/hmg/ddu009.
17.	Dai X, Pang S, Wang J, et al. Photoreceptor degeneration in a new Cacna1f mutant mouse model[J]. Exp Eye Res, 2019, 179: 106-114. DOI: 10.1016/j.exer.2018.11.010.

1. 苏钰, 文峰, 易长贤. 先天性静止性夜盲[M]//文峰, 易长贤. 临床眼底病·内科卷. 北京: 人民卫生出版社, 2015: 533-537.Su Y, Wen F, Yi CX. Congenital stationary night blindness[M]//Wen F, Yi CX. Clinical ophthalmic disease (internal medicine volume). Beijing: People's Medical Publishing House, 2015: 533-537.
2. De Silva SR, Arno G, Robson AG, et al. The X-linked retinopathies: physiological insights, pathogenic mechanisms, phenotypic features and novel therapies[J/OL]. Prog Retin Eye Res, 2021, 82: 100898[2020-08-06]. https://pubmed.ncbi.nlm.nih.gov/32860923/. DOI: 10.1016/j.preteyeres.2020.100898.
3. Zeitz C, Robson AG, Audo I. Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms[J]. Prog Retin Eye Res, 2015, 45: 58-110. DOI: 10.1016/j.preteyeres.2014.09.001.
4. Almutairi F, Almeshari N, Ahmad K, et al. Congenital stationary night blindness: an update and review of the disease spectrum in Saudi Arabia[J]. Acta Ophthalmologica, 2021, 99(6): 581-591. DOI: 10.1111/aos.14693.
5. Hove MN, Kilic-Biyik KZ, Trotter A, et al. Clinical characteristics, mutation spectrum, and prevalence of Åland eye disease/incomplete congenital stationary night blindness in Denmark[J]. Invest Ophthalmol Vis Sci, 2016, 57(15): 6861-6869. DOI: 10.1167/iovs.16-19445.
6. Kim HM, Joo K, Han J, et al. Clinical and genetic characteristics of Korean congenital stationary night blindness patients[J]. Genes (Basel), 2021, 12(6): 789. DOI: 10.3390/genes12060789.
7. Zeitz C, Michiels C, Neuillé M, et al. Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders[J]. Human Mutation, 2019, 40(6): 765-787. DOI: 10.1002/humu.23735.
8. Mahmood U, Méjécase C, Ali SMA, et al. A novel splice-site variant in CACNA1F causes a phenotype synonymous with Åland island eye disease and incomplete congenital stationary night blindness[J]. Genes (Basel), 2021, 12(2): 171. DOI: 10.3390/genes12020171.
9. 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.
10. RIGGS LA. Electroretinography in cases of night blindness[J]. Am J Ophthalmol, 1954, 38(1: 2): 70-78. DOI: 10.1016/0002-9394(54)90011-2.
11. 睢瑞芳, 李凤荣, 赵家良, 等. 完全型X连锁先天性静止性夜盲临床和基因研究[J]. 中华眼底病杂志, 2007, 23(3): 184-188. DOI: 10.3760/j.issn:1005-1015.2007.03.009.Sui RF, Li FR, Zhao JL, et al. Clinical and genetic study of complete X-linked congenital quiescent night blindness[J]. Chin J Ocul Fundus Dis, 2007, 23(3): 184-188. DOI: 10.3760/j.issn:1005-1015.2007.03.009.
12. Matthews G, Fuchs P. The diverse roles of ribbon synapses in sensory neurotransmission[J]. Nat Rev Neurosci, 2010, 11(12): 812-822. DOI: 10.1038/nrn2924.
13. Chang B, Heckenlively JR, Bayley PR, et al. The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses[J]. Vis Neurosci, 2006, 23(1): 11-24. DOI: 10.1017/S095252380623102X.
14. Bech-Hansen NT, Naylor MJ, Maybaum TA, et al. Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness[J]. Nat Genet, 1998, 19(3): 264-267. DOI: 10.1038/947.
15. Koschak A, Fernandez-Quintero ML, Heigl T, et al. Cav1.4 dysfunction and congenital stationary night blindness type 2[J]. Pflugers Arch, 2021, 473(9): 1437-1454. DOI: 10.1007/s00424-021-02570-x.
16. Jia S, Muto A, Orisme W, et al. Zebrafish Cacna1fa is required for cone photoreceptor function and synaptic ribbon formation[J]. Hum Mol Genet, 2014, 23(11): 2981-2994. DOI: 10.1093/hmg/ddu009.
17. Dai X, Pang S, Wang J, et al. Photoreceptor degeneration in a new Cacna1f mutant mouse model[J]. Exp Eye Res, 2019, 179: 106-114. DOI: 10.1016/j.exer.2018.11.010.

Chinese Journal of Ocular Fundus Diseases

Genetic analysis of the CACNA1F gene in a family affected with incomplete form Schubert-Bornschein type congenital stationary night blindness

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content