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Variations in opsin coding sequences cause x-linked cone dysfunction syndrome with myopia and dichromacy.

ABSTRACT: PURPOSE:To determine the role of variant L opsin haplotypes in seven families with Bornholm Eye Disease (BED), a cone dysfunction syndrome with dichromacy and myopia. METHODS:Analysis of the opsin genes within the L/M opsin array at Xq28 included cloning and sequencing of an exon 3-5 gene fragment, long range PCR to establish gene order, and quantitative PCR to establish gene copy number. In vitro expression of normal and variant opsins was performed to examine cellular trafficking and spectral sensitivity of pigments. RESULTS:All except one of the BED families possessed L opsin genes that contained a rare exon 3 haplotype. The exception was a family with the deleterious Cys203Arg substitution. Two rare exon 3 haplotypes were found and, where determined, these variant opsin genes were in the first position in the array. In vitro expression in transfected cultured neuronal cells showed that the variant opsins formed functional pigments, which trafficked to the cell membranes. The variant opsins were, however, less stable than wild type. CONCLUSIONS:It is concluded that the variant L opsin haplotypes underlie BED. The reduction in the amount of variant opsin produced in vitro compared with wild type indicates a possible disease mechanism. Alternatively, the recently identified defective splicing of exon 3 of the variant opsin transcript may be involved. Both mechanisms explain the presence of dichromacy and cone dystrophy. Abnormal pigment may also underlie the myopia that is invariably present in BED subjects.

SUBMITTER: McClements M

PROVIDER: S-EPMC3597186 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Variations in opsin coding sequences cause x-linked cone dysfunction syndrome with myopia and dichromacy.

McClements Michelle M Davies Wayne I L WI Michaelides Michel M Young Terri T Neitz Maureen M MacLaren Robert E RE Moore Anthony T AT Hunt David M DM

Investigative ophthalmology & visual science 20130215 2

<h4>Purpose</h4>To determine the role of variant L opsin haplotypes in seven families with Bornholm Eye Disease (BED), a cone dysfunction syndrome with dichromacy and myopia.<h4>Methods</h4>Analysis of the opsin genes within the L/M opsin array at Xq28 included cloning and sequencing of an exon 3-5 gene fragment, long range PCR to establish gene order, and quantitative PCR to establish gene copy number. In vitro expression of normal and variant opsins was performed to examine cellular traffickin ...[more]

PMID: 23322568

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Project description:To identify genetic mutations in three families with early onset high myopia (eoHM) limited to female members.Genomic DNA was collected from participating members of families XF1, XF2, and XF3. Genome-wide linkage scans were performed on the largest family (XF1). Whole exome sequencing was performed on seven samples, including five samples (four affected and one unaffected) from family XF1, as well as the two probands from family XF2 and XF3. Variants were analyzed with multistep bioinformatics analyses. Sanger-dideoxy sequencing was used to verify candidate variations in families and controls.The genome-wide linkage scans performed on family XF1 detected a candidate locus on chromosome Xp11.1-Xq13.3 with a maximum logarithm of the odds (LOD) score of 2.48 and 3.01 for markers DXS991 and DXS986, respectively. Parallel whole exome sequencing identified a novel c.893C>A (p.Ala298Asp) mutation in ARR3 located on Xq13.1 in family XF1, which was shared by all four affected individuals but not the unaffected individual. Two other novel mutations in ARR3, c.298C>T (p.Arg100*) and c.239T>C (p.Leu80Pro), were detected in families XF2 and XF3, respectively. These mutations were predicted to be damaging and were not present in the normal controls and existing databases. All three mutations cosegregated with eoHM in each of the three families, in which all heterozygous female members are affected whereas all hemizygous male family members are not affected. Transmission of the mutations and eoHM in the three families demonstrates an unusual pattern of X-linked female-limited inheritance.These data suggest that heterozygous mutations in ARR3 might be responsible for X-linked female-limited eoHM in the three families, a pattern contrary to the standard X-linked recessive trait. To our knowledge, eoHM is the first human disease associated with mutations in ARR3 and the second X-linked female-limited disease identified thus far. Identification of ARR3 associated with X-linked female-limited trait provides not only additional evidence of this unusual hereditary pattern but also an additional model for investigating the molecular mechanism responsible for female-limited phenotypes.

Dataset Information

Variations in opsin coding sequences cause x-linked cone dysfunction syndrome with myopia and dichromacy.

Publications

Variations in opsin coding sequences cause x-linked cone dysfunction syndrome with myopia and dichromacy.

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