Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X

Orosz, Orsolya; Rajta, I.; Vajas, Attila; Takács, Lili; Csutak, Adrienne; Fodor, Mariann; Kolozsvári, Bence Lajos; Resch, Miklós; Sényi, K.; Lesch, Balázs; Szabó, Viktória; Berta, András; Balogh, István; Losonczy, Gergely

doi:10.1167/iovs.16-21405

Cited by 23 publications

(22 citation statements)

References 40 publications

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“…It is well known that high-grade myopia is associated with rare interchange exon 3 haplotypes, such as LVAV A and LIAVA, of the L or M opsin genes ( Carroll et al, 2012 ; Greenwald et al, 2017 ; McClements et al, 2013 ; Orosz et al, 2017 ) (none in our sample; Table 3 ), resulting in incorrect splicing of exon 3 and greatly reduced amount of functional opsin in the cones harbouring the mutation. Eye growth associated with rare interchange haplotypes is suggested to be caused by erroneous contrast signals produced by mosaics with both normal cones and cones with mutant opsins ( Greenwald et al, 2017 ; Patterson et al, 2018 ).…”

Section: Discussionmentioning

confidence: 90%

“…There is evidence for this in the fact that there is a lower prevalence of myopia in red-green colour vision deficient students, who have highly skewed L:M cone ratios as a consequence of lacking L or M cones ( Ostadimoghaddam et al, 2014 ; Qian et al, 2009 ). Further evidence is the association between myopia and rare interchange haplotypes in exon 3 of the L and M cone opsin genes at chromosome location Xq28 (designated OPN1LW and OPN1MW, respectively) ( Carroll et al, 2012 ; Greenwald, Kuchenbecker, Rowlan, Neitz, & Neitz, 2017 ; McClements et al, 2013 ; Orosz et al, 2017 ). The highly variable nucleotide sequences in humans control the spectral tuning of the opsin and affect other aspects of protein structure and function, such as proper splicing of exon 3 in the precursor messenger RNA (pre-mRNA) ( Greenwald et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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The association between L:M cone ratio, cone opsin genes and myopia susceptibility

et al. 2019

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In syndromic forms of myopia caused by long (L) to middle (M) wavelength (L/M) interchange mutations, erroneous contrast signals from ON-bipolar cells activated by cones with different levels of opsin expression are suggested to make the eye susceptible to increased growth. This susceptibility is modulated by the L:M cone ratio. Here, we examined L and M opsin genes, L:M cone ratios and their association with common refractive errors in a population with low myopia prevalence. Cycloplegic autorefraction and ocular biometry were obtained for Norwegian genetically-confirmed normal trichromats. L:M cone ratios were estimated from spectral sensitivity functions measured with full-field ERG, after adjusting for individual differences in the wavelength of peak absorption deduced from cone opsin genetics. Mean L:M cone ratios and the frequency of alanine at L opsin position 180 were higher in males than what has been reported in males in populations with high myopia prevalence. High L:M cone ratios in females were associated with lower degree of myopia, and myopia was more frequent in females who were heterozygous for L opsin exon 3 haplotypes than in those who were homozygous. The results suggest that the L:M cone ratio, combined with milder versions of L opsin gene polymorphisms, may play a role in common myopia. This may in part explain the low myopia prevalence in Norwegian adolescents and why myopia prevalence was higher in females who were heterozygous for the L opsin exon 3 haplotype, since females are twice as likely to have genetic polymorphisms carried on the X-chromosome.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

The association between L:M cone ratio, cone opsin genes and myopia susceptibility

et al. 2019

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“…The molecular complexity of the L-and M-cone opsin genes (OPN1LW and OPN1MW) has been explored not only to understand the basis of color vision but also to elucidate the molecular genetic causes of X-linked cone diseases. 1,3,6,9,10,11,[26][27][28][29] BCM causes decreased L/M-cone vision due to simultaneous OPN1LW and OPN1MW gene defects as a result of one of multiple mutation mechanisms, such as large deletions involving upstream regulatory sequences (i.e., locus control region and promoters) and/or parts of or the entire OPN1LW and OPN1MW genes, missense mutations or nonsense mutations, and L/M interchange mutations. 7,9,26,[30][31][32] Among the more common genotypes reported are large deletions and the C203R missense mutation.…”

Section: Discussionmentioning

confidence: 99%

Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations

Sumaroka

Garafalo

Cideciyan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To compare the phenotype of blue cone monochromacy (BCM) caused by large deletion mutations with those having the C203R missense mutation. METHODS. BCM patients with large deletion mutations (n ¼ 21; age range, 5-60 years), and with the C203R missense mutation (n ¼ 13; age range, 5-70 years), were studied with optical coherence tomography, visual acuity, and perimetric sensitivity in a retrospective observational case series. Perceptual estimates of spatial resolution driven by rods, Scones , and L/M-cones were obtained by the choice of chromatic gratings presented on varied adapting conditions with a modified microperimeter. RESULTS. Both genotypes had abnormal foveal photoreceptor structure early in life. Patients with the C203R mutation, however, had decades-longer persistence of foveal photoreceptor outer nuclear layer thickness and a slower rate of development of inner segment/outer segment defects than did patients with large deletion mutations. At late ages, both genotypes had comparably severe losses of central structure. At the rod-rich hot spot, there was no difference in structure between cohorts with age. Grating acuities in all BCM patients were driven by Scones and rods; the foveal structural differences were not reflected in a difference between cohorts in visual sensitivity and spatial resolution. CONCLUSIONS. A difference in structural phenotype due to the C203R mutation versus large deletion mutations in BCM was detected as a more prolonged persistence of foveal photoreceptor structure in patients with the missense mutation. This should be taken into account in planning natural history studies, selecting outcomes for clinical trials, and defining the time window for possible therapies.

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“…Clinical exome sequencing was performed as described previously [36]. More than 95% of the target sequence was covered at least 20-fold.…”

Section: Clinical Exome Sequencingmentioning

confidence: 99%

Comprehensive genetic testing in children with a clinical diagnosis of ARPKD identifies phenocopies

et al. 2018

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Myopia and Late-Onset Progressive Cone Dystrophy Associate to LVAVA/MVAVA Exon 3 Interchange Haplotypes of Opsin Genes on Chromosome X

Cited by 23 publications

References 40 publications

The association between L:M cone ratio, cone opsin genes and myopia susceptibility

The association between L:M cone ratio, cone opsin genes and myopia susceptibility

Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations

Comprehensive genetic testing in children with a clinical diagnosis of ARPKD identifies phenocopies

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