Unraveling the Genetic Mystery: ATF6 Mutation in Achromatopsia

Hayat Ahmad Khan,*

*Correspondence to: Hayat Ahmad Khan.

Copyright

© 2024 Hayat Ahmad Khan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original   work is properly cited.

Received: 26 February 2024

Published: 12 April 2024

Introduction

Achromatopsia is an exceptionally rare early-onset retinal disorder inherited in an autosomal recessive pattern, characterized by the absence of cone photoreceptor function. This leads to a plethora of visual impairments including photophobia, nystagmus, color blindness, and markedly reduced visual acuity. The identification of the specific gene mutation in affected individuals is imperative for potential involvement in molecular genetic treatment trials. While the literature has identified causative gene mutations in five known genes (CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H), a significant portion of cases remain genetically unresolved. Recently, the discovery of ATF6 as a novel gene implicated in Achromatopsia has emerged, shedding light on previously unexplained cases.

Clinical Presentation

Our case involves a 21-year-old patient who presented with a longstanding history of poor vision, photophobia, color blindness, and nystagmus. Interestingly, there was no reported history of nyctalopia, distinguishing our case from certain forms of retinal dystrophies. Past ocular history revealed a diagnosis of macular bull's maculopathy, a common clinical finding in Achromatopsia, further confirming the diagnosis. Notably, positive family history was reported, with two siblings experiencing similar visual impairments, indicating a potential genetic predisposition.

Upon examination, the patient exhibited significantly reduced visual acuity bilaterally, with the right eye measuring 0.15 and the left eye measuring 0.3. The pupils demonstrated normal size, shape, and reaction to light, ruling out afferent pupil defects. Confrontation visual fields were full to finger count, suggesting preserved peripheral vision. However, a right eye exotropia was noted for both near and distance vision, accompanied by pendular nystagmus that increased in right gaze, with a null point observed in the left gaze position.

Of particular interest was the Ishihara color vision test, which revealed a score of 1/17 plates in both eyes, consistent with the classic color blindness associated with Achromatopsia. Slit lamp examination of the anterior segment revealed no abnormalities, except for photophobia, a common complaint in patients with Achromatopsia. Funduscopic examination unveiled a clear vitreous with a normal appearing optic disc and cup-to-disc ratio of 0.3. However, macular atrophy in a bull's eye pattern, characterized by atrophic punched-out lesions with pigmented margins in both eyes. The picture was symmetrical in both eyes. Fundus also show normal vasculature and peripheral retina, was observed bilaterally.

Cycloplegic refraction show moderate compound myopic astigmatism. Further imaging with spectral-domain optical coherence tomography (SD-OCT) revealed loss of cone inner and outer segments, interruption of the ciliary layer, and disruption of the retinal pigment epithelium (RPE) layer in the foveal area. Additionally, a shallow contour of the foveal pit was noted, consistent with foveal hypoplasia, a hallmark of Achromatopsia. Electroretinography (ERG) confirmed abnormal cone responses and a marked delay in implicit time, further corroborating the clinical diagnosis.

Genetic Analysis:

Genetic testing was performed, revealing a pathogenic variant in exon 10 of ATF6, specifically the variant c.1241_1242insA p.413Gin_414ArgPheSer (HGVS: c.1243dup, p.(Arg415Lysfs10)), in a homozygous state. This variant results in a premature stop codon, leading to either mRNA degradation (nonsense-mediated decay) or truncation of the ATF6 protein. This finding represents a significant addition to the genetic landscape of Achromatopsia and provides valuable insight into the molecular mechanisms underlying the disorder.

Comparison with Previous Reports:

Our case adds to the growing body of literature on Achromatopsia by presenting a novel variant in ATF6 associated with the disorder. Compared to previously reported cases, our patient exhibited similar clinical features including photophobia, nystagmus, color blindness, and reduced visual acuity. However, our case lacked nyctalopia, a symptom commonly observed in certain forms of retinal dystrophies, thus highlighting a distinct clinical presentation.

Notably, the identification of ATF6 as a causative gene in Achromatopsia expands our understanding of the genetic basis of the disorder. Previous studies have primarily focused on mutations in genes associated with phototransduction, such as CNGA3 and CNGB3. However, the discovery of ATF6 as a novel candidate gene underscores the complexity of Achromatopsia and the diverse molecular pathways involved in its pathogenesis.

Table 1: Summary of identified ATF6 disease alleles

Figure 1: Clinical findings for the patient with novel pathogenic variant in exon 10 of ATF6. Fundus images of right and left eyes of the patient showed normal optic discs and severe macular atrophy (A & B).

Figure 2: Spectral domain OCT images for the patient with novel pathogenic variant in exon 10 of ATF6. showed foveal atrophic patch size of optic disc in right (top) and left (bottom) eyes (A & B). The outer segments were disrupted at the fovea region (arrowheads) in both eyes (C & D).

Conclusion

In conclusion, our report highlights the clinical and genetic features of a rare case of Achromatopsia caused by a novel variant in ATF6. The identification of this variant expands our understanding of the genetic landscape of Achromatopsia and underscores the importance of genetic analysis in diagnosis and management. Further research is warranted to elucidate the molecular mechanisms underlying ATF6-associated Achromatopsia and to explore potential therapeutic interventions targeting this pathway.

Additional Report

Ahmad Al Moujahed reported two siblings from a consanguineous family of Arab descent diagnosed with ACHM. They identified a homozygous mutation in the exon 10 of the ATF6 gene c.1243dup, which leads to the introduction of a premature stop codon p.(Arg415Lysfs10) in the new coding frame. This premature stop codon is located 534 nucleotides from the last exon-exon junction and satisfies the >60-65 nucleotide criteria for transcripts that are subject to nonsense-mediated decay (NMD). The report concluded a new homozygous single-nucleotide duplication mutation in the ATF6 gene c.1243dup in 2 patients with achromatopsia that leads to a premature stop codon. The predicted regulation of this ATF6-achromatopsia allele by NMD of the variant transcript mRNA was also demonstrated.

This comprehensive article encompasses the clinical, genetic, and additional findings related to Achromatopsia, contributing to the ongoing understanding and management of this rare retinal disorder.

References

1. Ahmad Al Moujahed; Lance Safarta; Douglas Vollrath; Jonathan Lin. A Novel ATF6-Achromatopsia Allele Regulated by Nonsense-Mediated mRNA Decay. Investigative Ophthalmology & Visual Science June 2022, Vol.63, 499 – A0076.

2. Eun-Jin Lee,et al. Multiexon deletion alleles of ATF6 linked to achromatopsia. JCI Insight. 2020 Apr 9; 5(7): e136041.

3. Aboshiha J, Dubis AM, Carroll J, Hardcastle AJ, Michaelides M. The cone dysfunction syndromes. Br J Ophthalmol. 2016;100(1):115–121. doi: 10.1136/bjophthalmol-2014-306505.

4. Hirji N, Aboshiha J, Georgiou M, Bainbridge J, Michaelides M. Achromatopsia: clinical features, molecular genetics, animal models and therapeutic options. Ophthalmic Genet. 2018;39(2):149–157. doi: 10.1080/13816810.2017.1418389.

5. Kohl S, et al. Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet. 2000;9(14):2107–2116. doi: 10.1093/hmg/9.14.2107.

6. Kohl S, et al. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet. 1998;19(3):257–259. doi: 10.1038/935.

7. Kohl S, et al. Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet. 2002;71(2):422–425. doi: 10.1086/341835.

8. Chang B, et al. A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci USA. 2009;106(46):19581–19586. doi: 10.1073/pnas.0907720106.

9. Kohl S, et al. A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia. Am J Hum Genet. 2012;91(3):527–532. doi: 10.1016/j.ajhg.2012.07.006.

10. Kohl S, et al. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet. 2015;47(7):757–765. doi: 10.1038/ng.3319.

11. Ansar M, et al. Mutation of ATF6 causes autosomal recessive achromatopsia. Hum Genet. 2015;134(9):941–950. doi: 10.1007/s00439-015-1571-4.

12. Mastey RR, et al. Characterization of retinal structure in ATF6-associated achromatopsia. Invest Ophthalmol Vis Sci. 2019;60(7):2631–2640. doi: 10.1167/iovs.19-27047.

13. Skorczyk-Werner A, et al. Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene. Eur J Hum Genet. 2017;25(11):1210–1216. doi: 10.1038/ejhg.2017.131.

14. Xu M, et al. ATF6 is mutated in early onset photoreceptor degeneration with macular involvement. Invest Ophthalmol Vis Sci. 2015;56(6):3889–3895. doi: 10.1167/iovs.15-16778.

15. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7.

16. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell. 1999;10(11):3787–3799. doi: 10.1091/mbc.10.11.3787.

17. Yoshida H, Haze K, Yanagi H, Yura T, Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem. 1998;273(50):33741–33749. doi: 10.1074/jbc.273.50.33741.

18. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–1086. doi: 10.1126/science.1209038.

19. Nadanaka S, Yoshida H, Mori K. Reduction of disulfide bridges in the lumenal domain of ATF6 in response to glucose starvation. Cell Struct Funct. 2006;31(2):127–134. doi: 10.1247/csf.06024.

20. Okada A, et al. OsTGAP1, a bZIP transcription factor, coordinately regulates the inductive production of diterpenoid phytoalexins in rice. J Biol Chem. 2009;284(39):26510–26518. doi: 10.1074/jbc.M109.036871.

21. Shen J, Snapp EL, Lippincott-Schwartz J, Prywes R. Stable binding of ATF6 to BiP in the endoplasmic reticulum stress response. Mol Cell Biol. 2005;25(3):921–932. doi: 10.1128/MCB.25.3.921-932.2005.

22. Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ, Prywes R. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem. 2000;275(35):27013–27020.

23. Chiang WC, et al. Achromatopsia mutations target sequential steps of ATF6 activation. Proc Natl Acad Sci USA. 2017;114(2):400–405. doi: 10.1073/pnas.1606387114.

24. Meex SJ, et al. The ATF6-Met[67]Val substitution is associated with increased plasma cholesterol levels. Arterioscler Thromb Vasc Biol. 2009;29(9):1322–1327. doi: 10.1161/ATVBAHA.108.180240