Original articleNovel Mutations and Electrophysiologic Findings in RGS9- and R9AP-Associated Retinal Dysfunction (Bradyopsia)
Section snippets
Patients and Methods
Eight individuals (2 Pakistani sisters, 4 British males, 1 British female, and 1 Afghani female) from 7 families with clinical evidence of cone dysfunction and normal color vision were identified. After informed consent was obtained, blood samples from affected and unaffected family members were taken for DNA extraction and subsequent mutation screening of both RGS9 and R9AP. In parallel, the Pakistani family with a structure powerful for autozygosity mapping also was screened using a
Clinical Assessment
Eight individuals from 7 families with clinical and electrophysiologic evidence of cone dysfunction and normal color vision were included in the study. All 8 subjects reported reduced central vision since childhood associated with mild photophobia and did not report any difficulty with night vision. None reported progression. Normal color vision was confirmed in all 8 patients. They had no nystagmus, and fundi were normal. All 8 patients had a phenotype in keeping with oligocone trichromacy—a
Discussion
This study assessed 8 patients from 7 families with evidence of a cone dysfunction syndrome associated with normal color vision and screened for both RGS9 and R9AP. Novel mutations in those genes were found, and new electrophysiologic features were identified.
Three subjects were found to harbor mutations in R9AP; 2 sisters were homozygous for a novel in-frame deletion (p.D32_Q34del), and a further novel nonsense homozygous mutation was identified in the third subject (p.G205fs). A fourth
References (22)
Visual excitation and recovery
J Biol Chem
(1991)- et al.
Specific binding of RGS9-Gbeta 5L to protein anchor in photoreceptor membranes greatly enhances its catalytic activity
J Biol Chem
(2002) - et al.
Activation of RGS9-1GTPase acceleration by its membrane anchor, R9AP
J Biol Chem
(2003) - et al.
Six patients with bradyopsia (slow vision): clinical features and course of the disease
Ophthalmology
(2007) - et al.
S-cone ERGs elicited by a simple technique in normals and in tritanopes
Vision Res
(1999) - et al.
Luminance noise and the rapid determination of discrimination ellipses in colour deficiency
Vision Res
(1994) - et al.
Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction
Methods Enzymol
(1987) - et al.
High expression levels in cones of RGS9, the predominant GTPase accelerating protein of rods
Proc Natl Acad Sci U S A
(1998) - et al.
The GTPase activating factor for transducin in rod photoreceptors is the complex between RGS9 and type 5 G protein beta subunit
Proc Natl Acad Sci U S A
(1999) - et al.
R9AP, a membrane anchor for the photoreceptor GTPase accelerating protein, RGS9-1
Proc Natl Acad Sci U S A
(2002)
RGS9-1 is required for normal inactivation of mouse cone phototransduction
Mol Vis [serial online]
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Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes
2024, Progress in Retinal and Eye ResearchClinical vision and molecular loss: Integrating visual psychophysics with molecular genetics reveals key details of normal and abnormal visual processing
2021, Progress in Retinal and Eye ResearchCitation Excerpt :Its loss results in a disease known as Bradyopsia or “slow vision” (Nishiguchi et al., 2004). Bradyopsia is a stationary disease with early childhood onset, mild photophobia, difficulty tracking moving objects, moderate reductions in spatial acuity, and ERG abnormalities; but with normal colour vision and normally appearing fundi (Cheng et al., 2007; Hartong et al., 2007; Michaelides et al., 2010; Nishiguchi et al., 2004). To investigate how visual processing in this patient depends on light intensity, flicker sensitivities were measured at the same four light levels as for normal observers—the Low, Medium-Low, Medium-High and High levels of the 650-nm stimulus.
Diseases associated with mutations in CNGA3: Genotype–phenotype correlation and diagnostic guideline
2019, Progress in Molecular Biology and Translational ScienceCitation Excerpt :A diagnosis of OCT is hardly applicable for these patients at infancy when the color vision test could not be performed. Apart from CNGA3, mutations in several other genes have also been identified in a few patients with OCT or similar phenotype (like bradyopsia), such as CNGB3,77 GNAT2,78 CEP290,79 RGS9, and R9AP80,81 (Table 1). For the six genes associated with ACHM and related retinal diseases, biallelic mutations in CNGA3 are most frequently reported in Caucasians, accounting for 72.9% families with mutations identified in the six genes (Fig. 2).
The clinical presentation of bradyopsia in children
2017, Journal of AAPOSCitation Excerpt :The finding of the same RGS9 mutation in all 3 families suggests that it represents a founder effect on the Arabian Peninsula. The literature describes 6 Dutch patients (5 families) homozygous for a recurrent RGS9 mutation,2 2 Pakistanis (1 family) homozygous for R9AP mutation,4 1 Afghani homozygous for R9AP mutation,4 1 Guatemalan homozygous for R9AP mutation,2 1 Chinese compound heterozygous for R9AP mutations,5 and 1 British compound heterozygous for RGS9 mutations.4 There are an additional 2 previously reported cases (2 families) that were originally diagnosed as cone-rod dystrophy and subsequently found to have homozygous RGS9 mutations by retinal dystrophy next-generation sequencing panels.
Inherited retinal disorders
2016, Taylor and Hoyt's Pediatric Ophthalmology and Strabismus, Fifth EditionRetinal Architecture in RGS9- and R9AP-Associated Retinal Dysfunction (Bradyopsia)
2015, American Journal of OphthalmologyCitation Excerpt :However, aforementioned electroretinograms to a red flash under dark adaptation, which in a normal subject gives an early cone system–derived response and a later rod system–derived response, are completely normal, showing that dark-adapted cones function normally, at least initially. Indeed, even dark-adapted 30 Hz flicker responses (albeit to a dim flash, with a short presentation time) are normal initially, but become undetectable after approximately 10 seconds of stimulation.3,10 These observations thereby are all in keeping with our findings that cones are not only present in normal density, but also capable of normal function, and thus potentially amenable to rescue.
Manuscript no. 2009-10.
Michel Michaelides and Zheng Li contributed equally to the work and therefore should be considered equivalent authors.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Supported by grants from the British Retinitis Pigmentosa Society; the Guide Dogs for the Blind Association; the National Institute for Health Research UK to the Biomedical Research Centre for Ophthalmology based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology; the European Commission (EVI-Genoret); and Fight for Sight (USA).