Identification of novel mutations by targeted exome sequencing and the genotype-phenotype assessment of patients with achromatopsia

Li, Fen‐Fen; Huang, Xiu‐Feng; Chen, Jie; Yu, Xudong; Zheng, Meiqin; Liu, Fan; Jin, Zi‐Bing; Gan, Dekang

doi:10.1186/s12967-015-0694-7

Cited by 10 publications

(4 citation statements)

References 25 publications

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“…Although the study was performed with a limited number of affected animals, we were able, through behavioral studies and ERG recordings, to confirm inherited day blindness in the affected animals. By a next-generation sequencing strategy and bioinformatics tools, as applied in other studies, 25 – 28 we pinpointed the causative missense mutation, which was located within the cGMP-binding domain of the ovine CNGA3 gene. It is worth noting that in vitro analysis has confirmed impaired function of human CNGA3 polypeptides carrying mutations at the cGMP-binding domain relative to the function of the wild-type polypeptide.…”

Section: Discussionmentioning

confidence: 99%

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

Gootwine

Abu-Siam²,

Obolensky

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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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.

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Section: Discussionmentioning

confidence: 99%

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

Gootwine

Abu-Siam²,

Obolensky

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…A multigene panel includes ATF6, CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and other genes of interest. Comprehensive genomic testing includes targeted exome [81], whole-exome, and whole-genome sequencing. This may be considered if other tests have not confirmed the diagnosis.…”

Section: Optical Coherence Tomography (Oct) Is a Great Instrumentmentioning

confidence: 99%

A Review of Achromatopsia

Martínez¹

2020

TOOAJ

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Congenital achromatopsia is a hereditary form of day blindness caused by cone photoreceptor dysfunction, with an incidence of approximately 1 in 30,000. This inherited disorder is characterized by a lack of color discrimination, nystagmus, photophobia, and low visual acuity (< 0.2). The most typical genetic mutations are autosomal recessive changes in CNGA3, CNGB3, GNAT2, PDE6H, PDE6C, or ATF6. It should not be confused with cerebral achromatopsia, which is an acquired form of total color blindness that can result from illness, trauma, or some other cause. Color plays an essential role in our lives. It can change actions, influence thinking, and cause reactions. As a powerful type of communication, color is irreplaceable. Green means "go" and red means "stop". Traffic lights send this global meaning. Color vision deficiency, creates challenges in the daily lives of those who have an insufficient visual sense.Purpose: The aim of this review is to examine the literature published on achromatopsia and summarize the diagnosis, management, genetic characteristics, and the recent advances in gene therapy.Conclusions: Congenital achromatopsia is a complex inherited disease. Management of achromatopsia is multifaceted. There is currently no cure for achromatopsia, although gene therapy is a therapeutic option already being studied in clinical trials. The most recent study in human adults can be classified as safe and positive in terms of efficacy.

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“…4 More Comprehensive Genomic Testing. More comprehensive genomic testing includes targeted exome, 29 whole-exome, and whole-genome sequencing. This may be considered if other tests have not confirmed the diagnosis.…”

Section: Genetic Testingmentioning

confidence: 99%

Diagnosis and Treatment Options for Achromatopsia: A Review of the Literature

Pascual-Camps¹,

Barranco-González²,

Aviñó-Martínez³

et al. 2018

J Pediatr Ophthalmol Strabismus

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Achromatopsia is a complex inherited retinal disease that affects the cone cell function. It is usually an autosomal-recessive disease and is characterized by pendular nystagmus, poor visual acuity, lack of color vision, and marked photophobia. CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6 gene mutations have been identified as associated with this disease. New diagnostic and therapeutic tools are being studied. Optical coherence tomography and fundus autofluorescence are important imaging techniques that provide significant information about the progression of the disease. The genetic approach for these patients is a current important issue and gene therapy is an ongoing therapeutic option already being studied in clinical trials. The purpose of this review was to survey the current knowledge on diagnosis and treatment options in achromatopsia. [J Pediatr Ophthalmol Strabismus. 2018;55(2):85-92.].

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Identification of novel mutations by targeted exome sequencing and the genotype-phenotype assessment of patients with achromatopsia

Cited by 10 publications

References 25 publications

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

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

A Review of Achromatopsia

Diagnosis and Treatment Options for Achromatopsia: A Review of the Literature

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