Achromatopsia Research Articles

Multimodal imaging including semiquantitative short-wavelength and near-infrared autofluorescence in achromatopsia

Multimodal imaging provides insights into phenotype and disease progression in inherited retinal disorders. Congenital achromatopsia (ACHM), a cone dysfunction syndrome, has been long considered a stable condition, but recent evidence suggests structural progression. With gene replacement strategies under development for ACHM, there is a critical need for imaging biomarkers to define progression patterns and follow therapy. Using semiquantitative plots, near-infrared (NIR-AF) and short-wavelength autofluorescence (SW-AF) were explored and correlated with clinical characteristics and retinal structure on optical coherence tomography (OCT). In sixteen ACHM patients with genetic confirmation (CNGA3, n = 8; CNGB3, n = 7; PDE6C, n = 1), semiquantitative plots allowed the detailed analysis of autofluorescence patterns, even in poorly fixating eyes. Twelve eyes showed perifoveal hyperautofluorescent rings on SW-AF, and 7 eyes had central hypoautofluorescent areas on NIR-AF, without association between these alterations (P = 0.57). Patients with central NIR-AF hypoautofluorescence were older (P = 0.004) and showed more advanced retinal alterations on OCT than those with normal NIR-AF (P = 0.051). NIR-AF hypoautofluorescence diameter was correlated to patient age (r = 0.63, P = 0.009), size of ellipsoid zone defect on OCT (r = 0.67, P = 0.005), but not to the size of SW-AF hyperautofluorescence (P = 0.27). These results demonstrate the interest of NIR-AF as imaging biomarker in ACHM, suggesting a relationship with age and disease progression.

Prevalence of Color Blindness in Undergraduates of Kathmandu University

Color blindness is X-linked recessive inherited disorder that occurs mostly in males and is transmitted through females. Many people with color blindness may remain undetected. Thus the present study aims to evaluate the incidence of color blindness among undergraduates of Kathmandu University. A cross-sectional study was conducted among 825 undergraduates, aged 17-25 years, from June to August 2018, in Kathmandu University, Kavre, Nepal. The Ishihara plates were used to evaluate the color vision of students under natural day light condition. Study revealed that 24 (2.9%) undergraduates were color blind which include 24 male (5%) and no female. Among the color blind, five (20.3%), three (12.5%), two (8.33%) and 14 (58.33%) males were the victims of deuteranomaly, deuteranopia, protanomalia and total color blindness respectively. Color blindness is prevalent among the Brahmin 10 (3.9%), followed by Chettri 10 (2.72%) and Newar 4 (2.24%). Prevalence of color blindness is found to be higher in males than females. Total color blindness is the most prevalent in our study. Screening enables the students to become aware of limitations and devise ways of overcoming them.

Rod Monochromatism (Achromatopsia).

Rod monochromatism (achromatopsia) is a congenital cone photoreceptor disorder, which is rare, affecting about 1 in 30,000 individuals. These patients have normal rod function but no detectable cone function; therefore, everything they see is in shades of gray (total color blindness). Patients usually present in infancy with nystagmus and photophobia. Vision is usually about 20/200 or worse; patients have a hyperopic refractive error. Some patients show paradoxical pupillary response; that is, the pupils dilate in bright light. Fundus examination is normal, though pigmentary mottling and atrophic changes may be observed at the macula. Incomplete achromatopsia: Patients in this group have somewhat better visual acuity, about 20/80 to 20/120, with some residual functioning of cone photoreceptors. This milder form allows some color discrimination. Complete achromatopsia: It occurs in about 4-10% of Pingelapese islanders, who live on one of the Eastern Caroline Islands of Micronesia.

Design and Development of AAV-based Gene Supplementation Therapies for Achromatopsia and Retinitis Pigmentosa.

Achromatopsia (ACHM) and retinitis pigmentosa (RP) are inherited disorders caused by mutations in cone and rod photoreceptor-specific genes, respectively. ACHM strongly impairs daylight vision, whereas RP initially affects night vision and daylight vision at later stages. Currently, gene supplementation therapies utilizing recombinant adeno-associated virus (rAAV) vectors are being developed for various forms of ACHM and RP. In this chapter, we describe the procedure of designing and developing specific and efficient rAAV vectors for cone- and rod-specific gene supplementation.

Ophthalmic features of cone-rod dystrophy caused by pathogenic variants in the ALMS1 gene.

We aim to describe ophthalmic characteristics and systemic findings in a cohort of seven patients with cone-rod retinal dystrophy (CORD) caused by pathogenic variants in the ALMS1 gene. Seven patients with Alström syndrome (ALMS) were included in the study. A comprehensive ophthalmological examination was performed, including best-corrected visual acuity (BCVA), a semiautomated kinetic visual field exam, colour vision testing, full-field electroretinography testing according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards, spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging, and slit lamp and dilated fundus examination. DNA samples were analysed using Sanger sequencing or exome sequencing. In our cohort, the ocular phenotype presented with a wide variability in retinal function and disease severity. However, age of symptom onset (i.e. nystagmus and photophobia) was at 6-9months in all patients. These symptoms mostly mislead to the diagnosis of congenital achromatopsia (ACHM), Leber congenital amaurosis (LCA), isolated CORD or Bardet-Biedl syndrome. The systemic manifestations in our cohort were highly variable. In summary, we can report that most of our ALMS patients primarily presented with nystagmus and severe photophobia since early childhood interestingly without night blindness in the absence of systemic symptoms. Only genetic testing analysing both nonsyndromic retinal disease (RD) genes and syndromic ciliopathy genes by comprehensive panel sequencing can result in the correct diagnosis, genetically and clinically, with important implication for the physical health of the individual.

A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290

Purpose: To identify the gene defect and to study the clinical characteristics and natural course of disease in a family originally diagnosed with oligocone trichromacy (OT), a rare congenital cone dysfunction syndrome. Methods: Extensive clinical and ophthalmologic assessment was performed on two siblings with OT and long-term follow up data were analyzed. Subsequently, whole exome sequencing (WES) and Sanger sequence analysis of CEP290 was performed in the two siblings. Additionally, the identified CEP290 mutations were analyzed in persons with achromatopsia (ACHM) (n = 23) and autosomal recessive or isolated cone dystrophy (CD; n = 145). Results: In the first decade of life, the siblings were diagnosed with OT based on low visual acuity, photophobia, nystagmus, and absent cone response on electroretinography , but with normal color discrimination. Over time, the phenotype of OT evolved to a progressive degenerative disease without any CEP290-associated non-ocular features. In both siblings, two nonsense mutations (c.451C>T; p.(Arg151*) and c.4723A>T; p.(Lys1575*)) in CEP290 were found. Previously, p.(Arg151*) was demonstrated to induce nonsense-mediated alternative splicing events leading to intact open reading frames of the resulting mRNA products (p.(Leu148_Glu165del) and p.(Leu148_Lys172del)). mRNA analysis for p.(Lys1575*) confirmed a suspected hypomorphic character, as exon 36 skipping was observed in a small fraction of CEP290 mRNA, resulting in a 36 aa in-frame deletion (p.(Glu1569_Trp1604del)). No additional cases carrying these variants were identified in the ACHM and CD cohorts. Conclusions: Compound heterozygous hypomorphic mutations in CEP290 may lead to a rare form of cone-dominated retinal dystrophy, a novel phenotype belonging to the CEP290-associated spectrum of ciliopathies. These findings provide insight into the effect of CEP290 mutations on the clinical phenotype.

A Quantitative and Qualitative Exploration of Photoaversion in Achromatopsia.

PurposePhotoaversion (PA) is a disabling and ubiquitous feature of achromatopsia (ACHM). We aimed to help define the characteristics of this important symptom, and present the first published assessment of its impact on patients' lives, as well as quantitative and qualitative PA assessments.MethodsMolecularly confirmed ACHM subjects were assessed for PA using four tasks: structured survey of patient experience, novel quantitative subjective measurement of PA, visual acuities in differing ambient lighting, and objective palpebral aperture-related PA testing.ResultsPhotoaversion in ACHM was found to be the most significant symptom for a substantial proportion (38%) of patients. A novel subjective PA measurement technique was developed and demonstrated fidelity with more invasive paradigms without exposing often very photosensitive patients to brighter light intensities used elsewhere. An objective PA measurement was also refined for use in trials, indicating that higher light intensities than previously published are likely to be needed. Monocular testing, as required for trials, was also validated for the first time.ConclusionsThis study offers new insights into PA in ACHM. It provides the first structured evidence of the great significance of this symptom to patients, suggesting that PA should be considered as an additional outcome measure in therapeutic trials. It also offers new insights into the characteristics of PA in ACHM, and describes both subjective and objective measures of PA that could be employed in clinical trials.

Mechanisms of mutant PDE6 proteins underlying retinal diseases

Mutations in PDE6 genes encoding the effector enzymes in rods and cones underlie severe retinal diseases including retinitis pigmentosa (RP), autosomal dominant congenital stationary night blindness (adCSNB), and achromatopsia (ACHM). Here we examined a spectrum of pathogenic missense mutations in PDE6 using the system based on co-expression of cone PDE6C with its specialized chaperone AIPL1 and the regulatory Pγ subunit as a potent co-chaperone. We uncovered two mechanisms of PDE6C mutations underlying ACHM: (a) folding defects leading to expression of catalytically inactive proteins and (b) markedly diminished ability of Pγ to co-chaperone mutant PDE6C proteins thereby dramatically reducing the levels of functional enzyme. The mechanism of the Rambusch adCSNB associated with the H258N substitution in PDE6B was probed through the analysis of the model mutant PDE6C-H262N. We identified two interrelated deficits of PDE6C-H262N: disruption of the inhibitory interaction of Pγ with mutant PDE6C that markedly reduced the ability of Pγ to augment the enzyme folding. Thus, we conclude that the Rambusch adCSNB is triggered by low levels of the constitutively active PDE6. Finally, we examined PDE6C-L858V, which models PDE6B-L854V, an RP-linked mutation that alters the protein isoprenyl modification. This analysis suggests that the type of prenyl modifications does not impact the folding of PDE6, but it modulates the enzyme affinity for its trafficking partner PDE6D. Hence, the pathogenicity of PDE6B-L854V likely arises from its trafficking deficiency. Taken together, our results demonstrate the effectiveness of the PDE6C expression system to evaluate pathogenicity and elucidate the mechanisms of PDE6 mutations in retinal diseases.

Gene Augmentation Therapy for a Missense Substitution in the cGMP-Binding Domain of Ovine CNGA3 Gene Restores Vision in Day-Blind Sheep.

PurposeApplying CNGA3 gene augmentation therapy to cure a novel causative mutation underlying achromatopsia (ACHM) in sheep.MethodsImpaired vision that spontaneously appeared in newborn lambs was characterized by behavioral, electroretinographic (ERG), and histologic techniques. Deep-sequencing reads of an affected lamb and an unaffected lamb were compared within conserved genomic regions orthologous to human genes involved in similar visual impairment. Observed nonsynonymous amino acid substitutions were classified by their deleteriousness score. The putative causative mutation was assessed by producing compound CNGA3 heterozygotes and applying gene augmentation therapy using the orthologous human cDNA.ResultsBehavioral assessment revealed day blindness, and subsequent ERG examination showed attenuated photopic responses. Histologic and immunohistochemical examination of affected sheep eyes did not reveal degeneration, and cone photoreceptors expressing CNGA3 were present. Bioinformatics and sequencing analyses suggested a c.1618G>A, p.Gly540Ser substitution in the GMP-binding domain of CNGA3 as the causative mutation. This was confirmed by genetic concordance test and by genetic complementation experiment: All five compound CNGA3 heterozygotes, carrying both p.Arg236* and p.Gly540Ser mutations in CNGA3, were day-blind. Furthermore, subretinal delivery of the intact human CNGA3 gene using an adeno-associated viral vector (AAV) restored photopic vision in two affected p.Gly540Ser homozygous rams.ConclusionsThe c.1618G>A, p.Gly540Ser substitution in CNGA3 was identified as the causative mutation for a novel form of ACHM in Awassi sheep. Gene augmentation therapy restored vision in the affected sheep. This novel mutation provides a large-animal model that is valid for most human CNGA3 ACHM patients; the majority of them carry missense rather than premature-termination mutations.

Gene therapy for achromatopsia.

The present review summarizes the current status of achromatopsia (ACHM) gene therapy-related research activities and provides an outlook for their clinical application. ACHM is an inherited eye disease characterized by a congenital absence of cone photoreceptor function. As a consequence, ACHM is associated with strongly impaired daylight vision, photophobia, nystagmus and a lack of color discrimination. Currently, six genes have been linked to ACHM. Up to 80% of the patients carry mutations in the genes CNGA3 and CNGB3 encoding the two subunits of the cone cyclic nucleotide-gated channel. Various animal models of the disease have been established and their characterization has helped to increase our understanding of the pathophysiology associated with ACHM. With the advent of adeno-associated virus vectors as valuable gene delivery tools for retinal photoreceptors, a number of promising gene supplementation therapy programs have been initiated. In recent years, huge progress has been made towards bringing a curative treatment for ACHM into clinics. The first clinical trials are ongoing or will be launched soon and are expected to contribute important data on the safety and efficacy of ACHM gene supplementation therapy.

Social priming of hemispatial neglect affects spatial coding: Evidence from the Simon task.

In the Simon effect (SE), choice reactions are fast if the location of the stimulus and the response correspond when stimulus location is task-irrelevant; therefore, the SE reflects the automatic processing of space. Priming of social concepts was found to affect automatic processing in the Stroop effect. We investigated whether spatial coding measured by the SE can be affected by the observer's mental state. We used two social priming manipulations of impairments: one involving spatial processing - hemispatial neglect (HN) and another involving color perception - achromatopsia (ACHM). In two experiments the SE was reduced in the "neglected" visual field (VF) under the HN, but not under the ACHM manipulation. Our results show that spatial coding is sensitive to spatial representations that are not derived from task-relevant parameters, but from the observer's cognitive state. These findings dispute stimulus-response interference models grounded on the idea of the automaticity of spatial processing.

Residual Foveal Cone Structure in CNGB3-Associated Achromatopsia.

PurposeCongenital achromatopsia (ACHM) is an autosomal recessive disorder in which cone function is absent or severely reduced. Gene therapy in animal models of ACHM have shown restoration of cone function, though translation of these results to humans relies, in part, on the presence of viable cone photoreceptors at the time of treatment. Here, we characterized residual cone structure in subjects with CNGB3-associated ACHM.MethodsHigh-resolution imaging (optical coherence tomography [OCT] and adaptive optics scanning light ophthalmoscopy [AOSLO]) was performed in 51 subjects with CNGB3-associated ACHM. Peak cone density and inter-cone spacing at the fovea was measured using split-detection AOSLO. Foveal outer nuclear layer thickness was measured in OCT images, and the integrity of the photoreceptor layer was assessed using a previously published OCT grading scheme.ResultsAnalyzable images of the foveal cones were obtained in 26 of 51 subjects, with nystagmus representing the major obstacle to obtaining high-quality images. Peak foveal cone density ranged from 7,273 to 53,554 cones/mm2, significantly lower than normal (range, 84,733–234,391 cones/mm2), with the remnant cones being either contiguously or sparsely arranged. Peak cone density was correlated with OCT integrity grade; however, there was overlap of the density ranges between OCT grades.ConclusionsThe degree of residual foveal cone structure varies greatly among subjects with CNGB3-associated ACHM. Such measurements may be useful in estimating the therapeutic potential of a given retina, providing affected individuals and physicians with valuable information to more accurately assess the risk-benefit ratio as they consider enrolling in experimental gene therapy trials. (www.clinicaltrials.gov, NCT01846052.)

Dissociations in Coherence Sensitivity Reveal Atypical Development of Cortical Visual Processing in Congenital Achromatopsia.

While basic visual functions have been described in subjects with congenital achromatopsia (ACHM), little is known about their mid- or high-level cortical visual processing. We compared midlevel cortical visual processing in ACHM subjects (n = 11) and controls (n = 20). Abilities to detect global form, global motion, and biological motion embedded in noise were tested across a range of light levels, including scotopic, in which both ACHM subjects and controls must rely on rods. Contrast sensitivity functions (CSFs) were also measured. Achromatopsia subjects showed differential impairments across tests. In scotopic conditions, global form was most impaired, while biological motion was normal. In a subset of three ACHM subjects with normal scotopic CSFs, two of the three showed global form perception worse than controls; all showed global motion comparable to controls; and strikingly, two of the three showed biological motion perception superior to controls. The cone signal appears to play a crucial role in the development of perception of global form, as in ACHM this is impaired even in scotopic conditions, in which controls also have to rely on rods, and even in ACHM subjects with no scotopic spatial vision loss. In contrast, the rod signal appears sufficient for the development of normal (or even superior) extrastriate biological motion perception. These results suggest that ACHM leads to atypical development of cortical vision, highlighting the need to better understand the potential for further reorganization of cortical visual processing following new therapies aimed at restoring cone function.

Reliability and Repeatability of Cone Density Measurements in Patients with Congenital Achromatopsia.

Adaptive optics scanning light ophthalmoscopy (AOSLO) allows non-invasive assessment of the cone photoreceptor mosaic. Confocal AOSLO imaging of patients with achromatopsia (ACHM) reveals an altered reflectivity of the remaining cone structure, making identification of the cells more challenging than in normal retinas. Recently, a "split-detector" AOSLO imaging method was shown to enable direct visualization of cone inner segments in patients with ACHM. Several studies have demonstrated gene replacement therapy effective in restoring cone function in animal models of ACHM and human trials have on the horizon, making the ability to reliably assess cone structure increasingly important. Here we sought to examine whether absolute estimates of cone density obtained from split-detector and confocal AOSLO images differed from one another and whether the inter- and intra-observer reliability is significantly different between these modes. These findings provide an important foundation for evaluating the role of these images as tools to assess the efficacy of future gene therapy trials.

Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment

Cyclic nucleotide-gated (CNG) ion channels are key mediators underlying signal transduction in retinal and olfactory receptors. Genetic defects in CNGA3 and CNGB3, encoding two structurally related subunits of cone CNG channels, lead to achromatopsia (ACHM). ACHM is a congenital, autosomal recessive retinal disorder that manifests by cone photoreceptor dysfunction, severely reduced visual acuity, impaired or complete color blindness and photophobia. Here, we report the first canine models for CNGA3-associated channelopathy caused by R424W or V644del mutations in the canine CNGA3 ortholog that accurately mimic the clinical and molecular features of human CNGA3-associated ACHM. These two spontaneous mutations exposed CNGA3 residues essential for the preservation of channel function and biogenesis. The CNGA3-R424W results in complete loss of cone function in vivo and channel activity confirmed by in vitro electrophysiology. Structural modeling and molecular dynamics (MD) simulations revealed R424-E306 salt bridge formation and its disruption with the R424W mutant. Reversal of charges in a CNGA3-R424E-E306R double mutant channel rescued cGMP-activated currents uncovering new insights into channel gating. The CNGA3-V644del affects the C-terminal leucine zipper (CLZ) domain destabilizing intersubunit interactions of the coiled-coil complex in the MD simulations; the in vitro experiments showed incompetent trimeric CNGA3 subunit assembly consistent with abnormal biogenesis of in vivo channels. These newly characterized large animal models not only provide a valuable system for studying cone-specific CNG channel function in health and disease, but also represent prime candidates for proof-of-concept studies of CNGA3 gene replacement therapy for ACHM patients.

Gene therapy approaches to restore retinal cGMP channel function

Vertebrate vision is based on light-mediated alterations of the cyclic GMP concentration in outer segments of retinal photoreceptors. These chemical signals are converted by cyclic nucleotide-gated (CNG) channels into electrical signals that are further processed within the retina and, finally, the visual cortex of the brain. Dysfunctional cGMP signaling is associated with visual impairment and has been identified in several types of inherited blinding diseases. In particular, loss-of-function mutations in CNG channel subunits expressed in cone and rod photoreceptors were identified to cause achromatopsia (total color blindness) and retinitis pigmentosa, respectively. Besides displaying functional defects, the pathologies of both diseases are characterized by retinal degeneration that may be triggered by profound alterations in the cGMP and Ca2+ homeostasis. Our laboratory has generated genetic mouse models to dissect the molecular pathways underlying the multifaceted pathomechanisms of achromatopsia and retinitis pigmentosa. Complementary to these studies viral expression vectors based on AAVs (adeno associated virus) have been developed to rescue vision in genetic mouse models. These gene therapy approaches have now evolved to a point that allows clinical application in human patients in the near future. Our current approaches in this exciting new field will be discussed.

Advances in genetic study of achromatopsia

Achromatopsia is a kind of autosomal recessive cone disorder. It occurs with nystagmus, photophobia, inability of color discrimination and severely reduced visual acuity. Five pathogenic genes had been reported to be associated with achromatopsia: cyclic nucleotide-gated(CNG)A3, CNGB3, guanine nucleotide binding protein alpha transduction active pepitide 2(GNAT2), phosphodiesterase (PDE)6C and PDE6H. They are crucial for cone phototransduction. Mutations of these genes can induce achromatopsia. Gene therapy, which can recover partial visual function, has been successfully used for the treatment of achromatopsia in animal model. Clinical features, pathogenic genes functions and mutations, the animal models and gene therapy of achromatopsia were reviewed. Key words: Achromatopsia; Mutation; Disease models, animal; Gene therapy

Mutation of ATF6 causes autosomal recessive achromatopsia.

Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1–q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single-base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-015-1571-4) contains supplementary material, which is available to authorized users.

Cyclic nucleotide-gated channels and retinal cone photoreceptor cells function

Cyclic nucleotide-gated (CNG) channels are ion channels which are activated by the binding of cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP), they play a central role in the signal transduction pathways of vision and olfaction.Six different genes encode CNG protein, containing four A subunits (A1-A4) and two B subunits (B1 and B3). CNGA3 and CNGB3 have been found to be implicated in achromatopsia-associated mutations.Recently, a huge amount of researches showed the good responses to gene therapy in achromatopsia animal models.This article briefly reviewed the physiological roles of CNG channel in retinal cone photoreceptor cells and the recent research achievements of gene therapy in CNG channel-deficient mouse models with achromatopsia. Key words: Cyclic nucleotide-gated channel; Retinal cone photoreceptor cells; Gene, knockout

Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.

Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype.