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Molaei Ramshe S, Zardadi S, Alehabib E, Nourinia R, Jamshidi J, Soosanabadi M, Darvish H. A Novel Ornithine Aminotransferase Splice Site Mutation Causes Vitamin B6-Responsive Gyrate Atrophy. JOVR [Internet]. 2024Mar.10 [cited 2024Apr.28];19(1):118–132. Available from: https://knepublishing.com/index.php/JOVR/article/view/15446
https://doi.org/10.18502/jovr.v19i1.15446
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authors
-
Samira Molaei Ramshe
Samira Molaei Ramshe
Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
-
Safoura Zardadi
Safoura Zardadi
Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
-
Elham Alehabib
Elham Alehabib
Student Research Committee, Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
-
Ramin Nourinia
Ramin Nourinia
Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
-
Javad Jamshidi
Javad Jamshidi
Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
-
Mohsen Soosanabadi
Mohsen Soosanabadi
Department of Medical Genetics, Semnan University of Medical Sciences, Semnan, Iran
-
Hossein Darvish
Hossein Darvish
Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
Published Date
- Mar 10, 2024
A Novel Ornithine Aminotransferase Splice Site Mutation Causes Vitamin B6-Responsive Gyrate Atrophy
Abstract
Purpose: Gyrate atrophy of the choroid and retina (GACR) is a rare congenital disorder and mutations in the ornithine aminotransferase (OAT) gene has been specified as the underlying cause. Patients show a high level of ornithine in body fluids which may be controlled by low protein diets. Pyridoxine (vitamin B6) supplementation may also be effective, however, most patients appear to be nonresponsive to this modality of treatment.
Case Report: Here, we report a characterized case of a vitamin B6-responsive GACR who had a splicing mutation in the OAT gene. The GACR diagnosis was confirmed through the clinical features, imaging, biochemical findings, and whole-exome sequencing (WES) results. WES data revealed the splicing mutation in intron 4 of the OAT gene (NM_001322967: c.425-1G>A).
Conclusion: Our knowledge about the diagnosis and treatment of GACR can be improved by identifying novel mutations in the OAT gene and accurate follow-up of the patients to determine how they respond to treatment.
Keywords:
Gyrate Atrophy, Mutation, Ornithine Aminotransferase, Vitamin B6
References
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2. Montioli R, Bellezza I, Desbats MA, Voltattorni CB, Salviati L, Cellini B. Deficit of human ornithine aminotransferase in gyrate atrophy: Molecular, cellular, and clinical aspects. Biochim Biophys Acta, Proteins Proteomics 2021;1869:140555.
3. Peltola KE, Jääskeläinen S, Heinonen OJ, Falck B, Näntö-Salonen K, Heinänen K, et al. Peripheral nervous system in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology 2002;59:735–740.
4. Cleary MA, Dorland L, De Koning TJ, Poll-The BT, Duran M, Mandell R, et al. Ornithine aminotransferase deficiency: Diagnostic difficulties in neonatal presentation. J Inherit Metab Dis 2005;28:673–679.
5. Skorczyk-Werner A, Raczynska D, Wawrocka A, Zholdybayeva D, Yakhiyayeva N, Krawczynski MR. The coincidence of two ultra-rare hereditary eye diseases: Gyrate atrophy and Kjer optic atrophy-a surprising diagnosis based on next-generation sequencing. Intractable Rare Dis Res 2021;10:202–206.
6. Mitchell GA, Loone JE, Brodysll LC, Steel G, Suchaneks M, Engelhardtsii JF, et al. Human Ornithine- &aminotransferase cdna cloning and analysis of the structural gene. J Biol Chem 1988;263:14288–14295.
7. Kennaway NG, Weleber RG, Buist NRM. Gyrate atrophy of the choroid and retina with hyperornithinemia: Biochemical and histologic studies and response to vitamin B6. Am J Hum Genet 1980;32:529–541.
8. Weleber RG, Kennaway NG. Clinical trial of vitamin B6 for gyrate atrophy of the choroid and retina. Ophthalmology 1981;88:316–324.
9. Santinelli R, Costagliola C, Tolone C, D’Aloia A, D’Avanzo A, Prisco F, et al. Low-protein diet and progression of retinal degeneration in gyrate atrophy of the choroid and retina: A twenty-six-year follow-up. J Inherit Metab Dis 2004;27:187–196.
10. Kaiser-Kupfer MI, Caruso RC, Valle D, Reed GF. Use of an arginine-restricted diet to slow progression of visual loss in patients with gyrate atrophy. Arch Ophthalmol 2004;122:982–984.
11. Kasenchak J, Vrabec T. Novel autosomal dominant retinitis pigmentosa (adrP) mutation with features of gyrate atrophy. Invest Ophthalmol Vis Sci 2016;57:126–126.
12. Doimo M, Desbats MA, Baldoin MC, Lenzini E, Basso G, Murphy E, et al. Functional analysis of missense mutations of OAT, causing gyrate atrophy of choroid and retina. Hum Mutat 2013;34:229–236.
13. Javadzadeh A, Gharabaghi D. Gyrate atrophy of the choroid and retina with hyper-ornithinemia responsive to vitamin B6: A case report. J Med Case Rep 2007;1:1–3.
14. Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, et al. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2013
15. Jalali H, Najafi M, Khoshaeen A, Mahdavi MR, Mahdavi M. First report of c. 425-1G> A mutation in ornithine aminotransferase gene causing gyrate atrophy of the choroid and retina with hyperornithinemia. Eur J Ophthalmol 2021;31:NP23–NP26.
16. Mitchell GA, Labuda D, Fontaine G, Saudubray JM, Bonnefont EP, Lyonne S, et al. Splice-mediated insertion of an Alu sequence inactivates ornithine aminotransferase: A role for Alu elements in human mutation. Proc Natl Acad Sci U S A 1991;88:815–819.
17. Mashima Y, Weleber RG, Kennaway NG, Inana G. A singlebase change at a splice acceptor site in the ornithine aminotransferase gene causes abnormal RNA splicing in gyrate atrophy. Hum Genet 1992;90:305–307.
18. Park JK, Herron BJ, O’Donnell JJ, Shih VE, Ramesh V. Three novel mutations of the ornithine aminotransferase (OAT) gene in gyrate atrophy. Genomics 1992;14:553–554.
19. Kim SJ, Lim DH, Kim JH, Kang SW. Gyrate atrophy of the choroid and retina diagnosed by ornithine-δ- aminotransferase gene analysis: A case report. Korean J Ophthalmol 2013;27:388–391.
20. Heller D, Weiner C, Nasie I, Anikster Y, Landau Y, Koren T, et al. Reversal of cystoid macular edema in gyrate atrophy patients. Ophthalmic Genet 2017;38:549–554.
21. Zubarioglu T, Kiykim E, Cansever MS, Aktuglu Zeybek C. Ornithine aminotransferase deficiency in differential diagnosis of neonatal hyperammonemia: A case with a novel OAT gene mutation. Indian J Pediatr 2016;83:754– 755.
22. Braun DA, Ishii Y, Walsh AM, Van Allen EM, Wu CJ, Shukla SA, et al. Clinical validation of PBRM1 alterations as a marker of immune checkpoint inhibitor response in renal cell carcinoma. JAMA Oncol 2019;5:1631–1633.
23. McClatchey AI, Kaufman DL, Berson EL, Tobin AJ, Shih VE, Gusella JF, et al. Splicing defect at the ornithine aminotransferase (OAT) locus in gyrate atrophy. Am J Hum Genet 1990;47:790–794.
24. Mashima Y, Shiono T, Tamai M, Inana G. Heterogeneity and uniqueness of ornithine aminotransferase mutations found in Japanese gyrate atrophy patients. Curr Eye Res 1996;15:792–796.
25. Mitchell GA, Brody LC, Looney J, Steel G, Suchanek M, Dowling C, et al. An initiator codon mutation in ornithine delta- aminotransferase causing gyrate atrophy of the choroid and retina. J Clin Invest 1988;81:630–633.
26. Kaiser-Kupfer MI, Valle DL. Clinical, biochemical, and therapeutic aspects of gyrate atrophy. Prog Retin Res 1987;6:179–206.
27. Sergouniotis PI, Davidson AE, Lenassi E, Devery SR, Moore AT, Webster AR. Retinal structure, function, and molecular pathologic features in gyrate atrophy. Ophthalmology 2012;119:596–605.
28. Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, et al. Ornithine δ-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem 1992;267:3302–3307.
29. Ramesh V, McClatchey AI, Ramesh N, Benoit LA, Berson EL, Shih VE, et al. Molecular basis of ornithine aminotransferase deficiency in B-6-responsive and - nonresponsive forms of gyrate atrophy. Proc Natl Acad Sci U S A 1988;85:3777–3780.
30. Berson EL, Schmidt SY, Shih VE. Ocular and biochemical abnormalities in gyrate atrophy of the choroid and retina. Ophthalmology 1978;85:1018–1027.
31. Mashima Y, Murakami A, Weleber RG, Kennaway NG, Clarke L, Shiono T, et al. Nonsense-codon mutations of the ornithine aminotransferase gene with decreased levels of mutant mRNA in gyrate atrophy. Am J Hum Genet 1992;51:81–91.
32. Huang J, Fu J, Fu S, Yang L, Nie K, Duan C, et al. Diagnostic value of a combination of next-generation sequencing, chorioretinal imaging and metabolic analysis: Lessons from a consanguineous Chinese family with gyrate atrophy of the choroid and retina stemming from a novel OAT variant. Br J Ophthalmol 2019;103:428–435.
33. Kobayashi T, Ogawa H, Kasahara M, Shiozawa Z, Matsuzawa T. A single amino acid substitution within the mature sequence of ornithine aminotransferase obstructs mitochondrial entry of the precursor. Am J Hum Genet 1995;57:284–291.
34. Nakajima H, Hayasaka S, Shiono T, Watanabe SI, Misuno K, Saito T, et al. A case of gyrate atrophy of the choroid and retina associated with hyperornithinemia. Jpn J Ophthalmol 1981;25:495–500.
35. Takahashi O, Hayasaka S, Kiyosawa M, Mizuno K, Saito T, Tada K, et al. Gyrate atrophy of choroid and retina complicated by vitreous hemorrhage. Jpn J Ophthalmol 1985;29:170–176.
36. Cui X, Jauregui R, Park KS, Tsang SH. Multimodal characterization of a novel mutation causing vitamin B6-responsive gyrate atrophy. Ophthalmic Genet 2018;39:512–516.
37. Park JK, O’Donnell JJ, Shih VE, Gusella JF, Ramesh V. A 15-bp deletion in exon 5 of the ornithine aminotransferase (OAT) locus associated with gyrate atrophy. Hum Mutat 1992;1:293–297.
38. Mashima Y, Shiono T, Inana G. Rapid and efficient molecular analysis of gyrate atrophy using denaturing gradient gel electrophoresis. Invest Ophthalmol Vis Sci 1994;35:1065–1070.
39. Katagiri S, Gekka T, Hayashi T, Ida H, Ohashi T, Eto Y, et al. OAT mutations and clinical features in two Japanese brothers with gyrate atrophy of the choroid and retina. Doc Ophthalmol 2014;128:137–148.
40. Renner AB, Walter A, Fiebig BS, Jägle H. Gyrate atrophy: Clinical and genetic findings in a female without arginine-restricted diet during her first 39 years of life and report of a new OAT gene mutation. Doc Ophthalmol 2012;125:81– 89.
41. Mitchell GA, Brody LC, Sipila I, Looney JE, Wong C, Engelhardt JF, et al. At least two mutant alleles of ornithine δ-aminotransferase cause gyrate atrophy of the choroid and retina in Finns. Proc Natl Acad Sci U S A 1989;86:197– 201.
42. Hayasaka S, Saito T, Nakajima H, Takaku Y, Shiono T, Mizuno K, et al. Gyrate atrophy with hyperornithinaemia: Different types of responsiveness to vitamin B6. Br J Ophthalmol 1981;65:478–483.
43. Michaud J, Brody LC, Steel G, Fontaine G, Martin LS, Valle D, et al. Strand-separating conformational polymorphism analysis: Efficacy of detection of point mutations in the human ornithine δ-aminotransferase gene. Genomics 1992;13:389–394.
44. Dietz HC, Valle D, Francomano CA, Kendzior RJ, Pyeritz RE, Cutting GR, et al. The skipping of constitutive exons in vivo induced by nonsense mutations. AAAS 2016;259:680–683.
45. Michaud J, Thompson GN, Brody LC, Steel G, Obie C, Fontaine G, et al. Pyridoxine-responsive gyrate atrophy of the choroid and retina: Clinical and biochemical correlates of the mutation A226V. Am J Hum Genet 1995;56:616– 622.
46. Ohkubo Y, Ueta A, Ito T, Sumi S, Yamada M, Ozawa K, et al. Vitamin B6-responsive ornithine aminotransferase deficiency with a novel mutation G237D. Tohoku J Exp Med 2005;205(4):335–342.
47. Zekušić M, Škaričić A, Fumić K, Rogić D, Žigman T, Petković Ramadža D, et al. Metabolic follow-up of a Croatian patient with gyrate atrophy and a new mutation in the OAT gene: A case report. Biochem Medica 2018;28:514–22.z
48. Mashima Y, Weleber RG, Kennaway NG, Inana G. Genotype–phenotype correlation of a pyridoxine responsive form of gyrate atrophy. Ophthalmic Genet 1999;20:219–224.
49. Inana G, Chambers C, Hotta Y, Inouye L, Filpula D, Pulford S, et al. Point mutation affecting processing of the ornithine aminotransferase precursor protein in gyrate atrophy. J Biol Chem 1989;264:17432–17436.
50. Casalino G, Pierro L, Manitto MP, Michaelides M, Bandello F. Resolution of cystoid macular edema following argininerestricted diet and vitamin B6 supplementation in a case of gyrate atrophy. JAAPOS 2018;22:321–323.
51. Ghosh A, Schlecht H, Heptinstall LE, Bassett JK, Cartwright E, Bhaskar SS, et al. Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing. Arch Dis Child 2017;102:1019–1029.
52. Michel M, Blatsios G, Scholl-Bürgi S, Entenmann A, Wernstedt A, Zschocke A, et al. Gyrate atrophy in 2 siblings–Ophthalmological findings and a new mutation. Klin Pädiatr 2015;227:296–298.
53. Montioli R, Paiardini A, Giardina G, Zanzoni S, Cutruzzola F, Cellini B, et al. R180T variant of δ-ornithine aminotransferase associated with gyrate atrophy: Biochemical, computational, X-ray and NMR studies provide insight into its catalytic features. Febs J 2019;286:2787–2798.
54. Kaufman DL, Ramesh V, McClatchey AI, Menkes JH, Tobin AJ. Detection of point mutations associated with genetic diseases by an exon scanning technique. Genomics 1990;8:656–663.
55. Sambuughin N, Mungunsukh O, Ren M, Capacchione JF, Horkayne-Szakaly I, Chuang K, et al. Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis. Mol Genet Metab 2018;16:76–81.
56. Montioli R, Desbats MA, Grottelli S, Doimo M, Bellezza I, Voltattorni CB, et al. Molecular and cellular basis of ornithine δ-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina. Biochim Biophys Acta Mol Basis Dis BBA-MOL BASIS DIS 2018;1864:3629–3638.
57. Vorechovsky I. Transposable elements in diseaseassociated cryptic exons. Hum Genet 2010;127:135–154.
2. Montioli R, Bellezza I, Desbats MA, Voltattorni CB, Salviati L, Cellini B. Deficit of human ornithine aminotransferase in gyrate atrophy: Molecular, cellular, and clinical aspects. Biochim Biophys Acta, Proteins Proteomics 2021;1869:140555.
3. Peltola KE, Jääskeläinen S, Heinonen OJ, Falck B, Näntö-Salonen K, Heinänen K, et al. Peripheral nervous system in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology 2002;59:735–740.
4. Cleary MA, Dorland L, De Koning TJ, Poll-The BT, Duran M, Mandell R, et al. Ornithine aminotransferase deficiency: Diagnostic difficulties in neonatal presentation. J Inherit Metab Dis 2005;28:673–679.
5. Skorczyk-Werner A, Raczynska D, Wawrocka A, Zholdybayeva D, Yakhiyayeva N, Krawczynski MR. The coincidence of two ultra-rare hereditary eye diseases: Gyrate atrophy and Kjer optic atrophy-a surprising diagnosis based on next-generation sequencing. Intractable Rare Dis Res 2021;10:202–206.
6. Mitchell GA, Loone JE, Brodysll LC, Steel G, Suchaneks M, Engelhardtsii JF, et al. Human Ornithine- &aminotransferase cdna cloning and analysis of the structural gene. J Biol Chem 1988;263:14288–14295.
7. Kennaway NG, Weleber RG, Buist NRM. Gyrate atrophy of the choroid and retina with hyperornithinemia: Biochemical and histologic studies and response to vitamin B6. Am J Hum Genet 1980;32:529–541.
8. Weleber RG, Kennaway NG. Clinical trial of vitamin B6 for gyrate atrophy of the choroid and retina. Ophthalmology 1981;88:316–324.
9. Santinelli R, Costagliola C, Tolone C, D’Aloia A, D’Avanzo A, Prisco F, et al. Low-protein diet and progression of retinal degeneration in gyrate atrophy of the choroid and retina: A twenty-six-year follow-up. J Inherit Metab Dis 2004;27:187–196.
10. Kaiser-Kupfer MI, Caruso RC, Valle D, Reed GF. Use of an arginine-restricted diet to slow progression of visual loss in patients with gyrate atrophy. Arch Ophthalmol 2004;122:982–984.
11. Kasenchak J, Vrabec T. Novel autosomal dominant retinitis pigmentosa (adrP) mutation with features of gyrate atrophy. Invest Ophthalmol Vis Sci 2016;57:126–126.
12. Doimo M, Desbats MA, Baldoin MC, Lenzini E, Basso G, Murphy E, et al. Functional analysis of missense mutations of OAT, causing gyrate atrophy of choroid and retina. Hum Mutat 2013;34:229–236.
13. Javadzadeh A, Gharabaghi D. Gyrate atrophy of the choroid and retina with hyper-ornithinemia responsive to vitamin B6: A case report. J Med Case Rep 2007;1:1–3.
14. Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, et al. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2013
15. Jalali H, Najafi M, Khoshaeen A, Mahdavi MR, Mahdavi M. First report of c. 425-1G> A mutation in ornithine aminotransferase gene causing gyrate atrophy of the choroid and retina with hyperornithinemia. Eur J Ophthalmol 2021;31:NP23–NP26.
16. Mitchell GA, Labuda D, Fontaine G, Saudubray JM, Bonnefont EP, Lyonne S, et al. Splice-mediated insertion of an Alu sequence inactivates ornithine aminotransferase: A role for Alu elements in human mutation. Proc Natl Acad Sci U S A 1991;88:815–819.
17. Mashima Y, Weleber RG, Kennaway NG, Inana G. A singlebase change at a splice acceptor site in the ornithine aminotransferase gene causes abnormal RNA splicing in gyrate atrophy. Hum Genet 1992;90:305–307.
18. Park JK, Herron BJ, O’Donnell JJ, Shih VE, Ramesh V. Three novel mutations of the ornithine aminotransferase (OAT) gene in gyrate atrophy. Genomics 1992;14:553–554.
19. Kim SJ, Lim DH, Kim JH, Kang SW. Gyrate atrophy of the choroid and retina diagnosed by ornithine-δ- aminotransferase gene analysis: A case report. Korean J Ophthalmol 2013;27:388–391.
20. Heller D, Weiner C, Nasie I, Anikster Y, Landau Y, Koren T, et al. Reversal of cystoid macular edema in gyrate atrophy patients. Ophthalmic Genet 2017;38:549–554.
21. Zubarioglu T, Kiykim E, Cansever MS, Aktuglu Zeybek C. Ornithine aminotransferase deficiency in differential diagnosis of neonatal hyperammonemia: A case with a novel OAT gene mutation. Indian J Pediatr 2016;83:754– 755.
22. Braun DA, Ishii Y, Walsh AM, Van Allen EM, Wu CJ, Shukla SA, et al. Clinical validation of PBRM1 alterations as a marker of immune checkpoint inhibitor response in renal cell carcinoma. JAMA Oncol 2019;5:1631–1633.
23. McClatchey AI, Kaufman DL, Berson EL, Tobin AJ, Shih VE, Gusella JF, et al. Splicing defect at the ornithine aminotransferase (OAT) locus in gyrate atrophy. Am J Hum Genet 1990;47:790–794.
24. Mashima Y, Shiono T, Tamai M, Inana G. Heterogeneity and uniqueness of ornithine aminotransferase mutations found in Japanese gyrate atrophy patients. Curr Eye Res 1996;15:792–796.
25. Mitchell GA, Brody LC, Looney J, Steel G, Suchanek M, Dowling C, et al. An initiator codon mutation in ornithine delta- aminotransferase causing gyrate atrophy of the choroid and retina. J Clin Invest 1988;81:630–633.
26. Kaiser-Kupfer MI, Valle DL. Clinical, biochemical, and therapeutic aspects of gyrate atrophy. Prog Retin Res 1987;6:179–206.
27. Sergouniotis PI, Davidson AE, Lenassi E, Devery SR, Moore AT, Webster AR. Retinal structure, function, and molecular pathologic features in gyrate atrophy. Ophthalmology 2012;119:596–605.
28. Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, et al. Ornithine δ-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem 1992;267:3302–3307.
29. Ramesh V, McClatchey AI, Ramesh N, Benoit LA, Berson EL, Shih VE, et al. Molecular basis of ornithine aminotransferase deficiency in B-6-responsive and - nonresponsive forms of gyrate atrophy. Proc Natl Acad Sci U S A 1988;85:3777–3780.
30. Berson EL, Schmidt SY, Shih VE. Ocular and biochemical abnormalities in gyrate atrophy of the choroid and retina. Ophthalmology 1978;85:1018–1027.
31. Mashima Y, Murakami A, Weleber RG, Kennaway NG, Clarke L, Shiono T, et al. Nonsense-codon mutations of the ornithine aminotransferase gene with decreased levels of mutant mRNA in gyrate atrophy. Am J Hum Genet 1992;51:81–91.
32. Huang J, Fu J, Fu S, Yang L, Nie K, Duan C, et al. Diagnostic value of a combination of next-generation sequencing, chorioretinal imaging and metabolic analysis: Lessons from a consanguineous Chinese family with gyrate atrophy of the choroid and retina stemming from a novel OAT variant. Br J Ophthalmol 2019;103:428–435.
33. Kobayashi T, Ogawa H, Kasahara M, Shiozawa Z, Matsuzawa T. A single amino acid substitution within the mature sequence of ornithine aminotransferase obstructs mitochondrial entry of the precursor. Am J Hum Genet 1995;57:284–291.
34. Nakajima H, Hayasaka S, Shiono T, Watanabe SI, Misuno K, Saito T, et al. A case of gyrate atrophy of the choroid and retina associated with hyperornithinemia. Jpn J Ophthalmol 1981;25:495–500.
35. Takahashi O, Hayasaka S, Kiyosawa M, Mizuno K, Saito T, Tada K, et al. Gyrate atrophy of choroid and retina complicated by vitreous hemorrhage. Jpn J Ophthalmol 1985;29:170–176.
36. Cui X, Jauregui R, Park KS, Tsang SH. Multimodal characterization of a novel mutation causing vitamin B6-responsive gyrate atrophy. Ophthalmic Genet 2018;39:512–516.
37. Park JK, O’Donnell JJ, Shih VE, Gusella JF, Ramesh V. A 15-bp deletion in exon 5 of the ornithine aminotransferase (OAT) locus associated with gyrate atrophy. Hum Mutat 1992;1:293–297.
38. Mashima Y, Shiono T, Inana G. Rapid and efficient molecular analysis of gyrate atrophy using denaturing gradient gel electrophoresis. Invest Ophthalmol Vis Sci 1994;35:1065–1070.
39. Katagiri S, Gekka T, Hayashi T, Ida H, Ohashi T, Eto Y, et al. OAT mutations and clinical features in two Japanese brothers with gyrate atrophy of the choroid and retina. Doc Ophthalmol 2014;128:137–148.
40. Renner AB, Walter A, Fiebig BS, Jägle H. Gyrate atrophy: Clinical and genetic findings in a female without arginine-restricted diet during her first 39 years of life and report of a new OAT gene mutation. Doc Ophthalmol 2012;125:81– 89.
41. Mitchell GA, Brody LC, Sipila I, Looney JE, Wong C, Engelhardt JF, et al. At least two mutant alleles of ornithine δ-aminotransferase cause gyrate atrophy of the choroid and retina in Finns. Proc Natl Acad Sci U S A 1989;86:197– 201.
42. Hayasaka S, Saito T, Nakajima H, Takaku Y, Shiono T, Mizuno K, et al. Gyrate atrophy with hyperornithinaemia: Different types of responsiveness to vitamin B6. Br J Ophthalmol 1981;65:478–483.
43. Michaud J, Brody LC, Steel G, Fontaine G, Martin LS, Valle D, et al. Strand-separating conformational polymorphism analysis: Efficacy of detection of point mutations in the human ornithine δ-aminotransferase gene. Genomics 1992;13:389–394.
44. Dietz HC, Valle D, Francomano CA, Kendzior RJ, Pyeritz RE, Cutting GR, et al. The skipping of constitutive exons in vivo induced by nonsense mutations. AAAS 2016;259:680–683.
45. Michaud J, Thompson GN, Brody LC, Steel G, Obie C, Fontaine G, et al. Pyridoxine-responsive gyrate atrophy of the choroid and retina: Clinical and biochemical correlates of the mutation A226V. Am J Hum Genet 1995;56:616– 622.
46. Ohkubo Y, Ueta A, Ito T, Sumi S, Yamada M, Ozawa K, et al. Vitamin B6-responsive ornithine aminotransferase deficiency with a novel mutation G237D. Tohoku J Exp Med 2005;205(4):335–342.
47. Zekušić M, Škaričić A, Fumić K, Rogić D, Žigman T, Petković Ramadža D, et al. Metabolic follow-up of a Croatian patient with gyrate atrophy and a new mutation in the OAT gene: A case report. Biochem Medica 2018;28:514–22.z
48. Mashima Y, Weleber RG, Kennaway NG, Inana G. Genotype–phenotype correlation of a pyridoxine responsive form of gyrate atrophy. Ophthalmic Genet 1999;20:219–224.
49. Inana G, Chambers C, Hotta Y, Inouye L, Filpula D, Pulford S, et al. Point mutation affecting processing of the ornithine aminotransferase precursor protein in gyrate atrophy. J Biol Chem 1989;264:17432–17436.
50. Casalino G, Pierro L, Manitto MP, Michaelides M, Bandello F. Resolution of cystoid macular edema following argininerestricted diet and vitamin B6 supplementation in a case of gyrate atrophy. JAAPOS 2018;22:321–323.
51. Ghosh A, Schlecht H, Heptinstall LE, Bassett JK, Cartwright E, Bhaskar SS, et al. Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing. Arch Dis Child 2017;102:1019–1029.
52. Michel M, Blatsios G, Scholl-Bürgi S, Entenmann A, Wernstedt A, Zschocke A, et al. Gyrate atrophy in 2 siblings–Ophthalmological findings and a new mutation. Klin Pädiatr 2015;227:296–298.
53. Montioli R, Paiardini A, Giardina G, Zanzoni S, Cutruzzola F, Cellini B, et al. R180T variant of δ-ornithine aminotransferase associated with gyrate atrophy: Biochemical, computational, X-ray and NMR studies provide insight into its catalytic features. Febs J 2019;286:2787–2798.
54. Kaufman DL, Ramesh V, McClatchey AI, Menkes JH, Tobin AJ. Detection of point mutations associated with genetic diseases by an exon scanning technique. Genomics 1990;8:656–663.
55. Sambuughin N, Mungunsukh O, Ren M, Capacchione JF, Horkayne-Szakaly I, Chuang K, et al. Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis. Mol Genet Metab 2018;16:76–81.
56. Montioli R, Desbats MA, Grottelli S, Doimo M, Bellezza I, Voltattorni CB, et al. Molecular and cellular basis of ornithine δ-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina. Biochim Biophys Acta Mol Basis Dis BBA-MOL BASIS DIS 2018;1864:3629–3638.
57. Vorechovsky I. Transposable elements in diseaseassociated cryptic exons. Hum Genet 2010;127:135–154.