De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy

Buena-Atienza, Elena; Rüther, Klaus; Baumann, Britta; Bergholz, Richard; Birch, David G.; Baere, Elfride De; Dollfus, Hélène; Greally, Marie T.; Gustavsson, Peter; Hamel, Christian; Heckenlively, John R.; Leroy, Bart P.; Plomp, Astrid S.; Pott, Jan Willem R.; Rose, Katherine; Rosenberg, Thomas; Stark, Zornitza; Verheij, Joanne; Weleber, Richard G.; Zobor, Ditta; Weisschuh, Nicole; Kohl, Susanne; Wissinger, Bernd

doi:10.1038/srep28253

Cited by 30 publications

(63 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…45 which was not observed in this study. Deletion of the last 72 nucleotides of exon 2 places a new splice site in codon 113, with a splice site between cDNA residues 337 and 338.…”

Section: Discussioncontrasting

confidence: 79%

Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations

Greenwald

Kuchenbecker

Rowlan

et al. 2017

Trans. Vis. Sci. Tech.

View full text Add to dashboard Cite

PurposeHuman long (L) and middle (M) wavelength cone opsin genes are highly variable due to intermixing. Two L/M cone opsin interchange mutants, designated LIAVA and LVAVA, are associated with clinical diagnoses, including red-green color vision deficiency, blue cone monochromacy, cone degeneration, myopia, and Bornholm Eye Disease. Because the protein and splicing codes are carried by the same nucleotides, intermixing L and M genes can cause disease by affecting protein structure and splicing.MethodsGenetically engineered mice were created to allow investigation of the consequences of altered protein structure alone, and the effects on cone morphology were examined using immunohistochemistry. In humans and mice, cone function was evaluated using the electroretinogram (ERG) under L/M- or short (S) wavelength cone isolating conditions. Effects of LIAVA and LVAVA genes on splicing were evaluated using a minigene assay.ResultsERGs and histology in mice revealed protein toxicity for the LVAVA but not for the LIAVA opsin. Minigene assays showed that the dominant messenger RNA (mRNA) was aberrantly spliced for both variants; however, the LVAVA gene produced a small but significant amount of full-length mRNA and LVAVA subjects had correspondingly reduced ERG amplitudes. In contrast, the LIAVA subject had no L/M cone ERG.ConclusionsDramatic differences in phenotype can result from seemingly minor differences in genotype through divergent effects on the dual amino acid and splicing codes.Translational RelevanceThe mechanism by which individual mutations contribute to clinical phenotypes provides valuable information for diagnosis and prognosis of vision disorders associated with L/M interchange mutations, and it informs strategies for developing therapies.

show abstract

“…45 which was not observed in this study. Deletion of the last 72 nucleotides of exon 2 places a new splice site in codon 113, with a splice site between cDNA residues 337 and 338.…”

Section: Discussioncontrasting

confidence: 79%

Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations

Greenwald

Kuchenbecker

Rowlan

et al. 2017

Trans. Vis. Sci. Tech.

View full text Add to dashboard Cite

show abstract

“…The third genotype involves inactivating mutations in both the L and M genes. Although the C203R mutation has been documented in this genotype 8 , 16 , 19 , the LIAVA haplotype (or a very similar haplotype) in exon 3 of both genes seems to be frequent 17 , 20 .…”

Section: Introductionmentioning

confidence: 74%

Genotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy

Katagiri

Iwasa

Hayashi

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Blue cone monochromacy (BCM) is characterized by loss of function of both OPN1LW (the first) and OPN1MW (the downstream) genes on the X chromosome. The purpose of this study was to investigate the first and downstream genes in the OPN1LW/OPN1MW array in four unrelated Japanese males with BCM. In Case 1, only one gene was present. Abnormalities were found in the promoter, which had a mixed unique profile of first and downstream gene promoters and a −71A > C substitution. As the promoter was active in the reporter assay, the cause of BCM remains unclear. In Case 2, the same novel mutation, M273K, was present in exon 5 of both genes in a two-gene array. The mutant pigments showed no absorbance at any of the wavelengths tested, suggesting that the mutation causes pigment dysfunction. Case 3 had a large deletion including the locus control region and entire first gene. Case 4 also had a large deletion involving exons 2–6 of the first gene. As an intact LCR was present upstream and one apparently normal downstream gene was present, BCM in Case 4 was not ascribed solely to the deletion. The deletions in Cases 3 and 4 were considered to have been caused by non-homologous recombination.

show abstract

“…We have previously described a de novo intrachromosomal gene conversion event in the male germline transferring a pathogenic haplotype from OPN1MW to OPN1LW [ 12 ]. Notwithstanding, the BCM patient’s grandfather presented with a linked colour vision deficiency due to a pathogenic haplotype in OPN1MW and the patient’s mother was a carrier of the converted OPN1LW gene [ 13 ]. Our case report herein describes a BCM patient bearing a unique mutation that stem from an independent de novo event in a family with no history of BCM or colour vision abnormalities.…”

Section: Discussionmentioning

confidence: 99%

A 73,128 bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case report

Buena-Atienza¹,

Nasser²,

Kohl³

et al. 2018

BMC Med Genet

Self Cite

View full text Add to dashboard Cite

BackgroundBlue Cone Monochromacy (BCM) is a rare congenital cone dysfunction disorder with X-linked recessive mode of inheritance. BCM is caused by mutations at the OPN1LW/MW cone opsin gene cluster including deletions of the locus control region (LCR) and/or parts of the gene cluster. We aimed at investigating the clinical presentation, genetic cause and inheritance underlying a sporadic case of BCM.Case presentationWe report a 24-year-old male presenting with congenital photophobia, nystagmus and colour vision abnormalities. There was no history of retinal dystrophy in the family. Clinical diagnosis of BCM was supported by genetic investigations of the patient and his family members. Molecular genetic analysis of the OPN1LW/OPN1MW gene cluster revealed a novel deletion of about 73 kb in the patient encompassing the LCR. The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather.ConclusionsThe present report provides the clinical findings and the genetic basis underlying a sporadic BCM case which is caused by a de novo deletion within the OPN1LW/MW gene cluster originating from the mother’s germline due to Alu-repeat mediated recombination. This is the first report of a de novo deletion resulting in BCM, highlighting the importance to consider BCM and perform genetic testing for this condition in male patients with cone dysfunction also in the absence of a positive family history.

show abstract

De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy

Cited by 30 publications

References 34 publications

Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations

Role of a Dual Splicing and Amino Acid Code in Myopia, Cone Dysfunction and Cone Dystrophy Associated with L/M Opsin Interchange Mutations

Genotype determination of the OPN1LW/OPN1MW genes: novel disease-causing mechanisms in Japanese patients with blue cone monochromacy

A 73,128 bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case report

Contact Info

Product

Resources

About