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Susanne Roosing, Ingeborgh L. van den Born, Alberta A. Thiadens, Carel B. Hoyng, Frans P. Cremers, Caroline C. Klaver, Anneke I. den Hollander; Maternal Uniparental Isodisomy Of Chromosome 6 Reveals A Tulp1 Mutation As A Novel Cause Of Cone Dysfunction. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4555.
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© ARVO (1962-2015); The Authors (2016-present)
The majority of the genetic causes of autosomal recessive cone dystrophy (arCD) is currently unknown. Therefore, we employed a high-resolution homozygosity mapping approach in a cohort of arCD patients to identify new genes for arCD.
A cohort of 83 arCD patients was genotyped with Affymetrix 5.0 SNP microarrays. Homozygous regions in the patients’ genomes were determined with Partek Genomics Solution software. One patient showed homozygosity of SNPs across chromosome 6. To test the possibility of uniparental isodisomy (UPD), segregation analysis was performed in family members of this patient using several microsatellite markers on chromosome 6. Direct sequencing of all retinal disease genes on chromosome 6 (ELOVL4, EYS, IMPG1, LCA5, RDS and TULP1) followed, and revealed a pathogenic TULP1 mutation in this patient. A cohort of 159 arCD patients was screened for this particular mutation using the restriction enzyme HhaI.Ophthalmic examination of these patients included electroretinography, perimetry, optical coherence tomography, fundus autofluorescence, and fundus photography.
Segregation analysis with microsatellite markers confirmed maternal UPD in this patient. Screening of TULP1 revealed a novel homozygous missense mutation (p.Arg420Ser), while no mutations were detected in other retinal disease genes on chromosome 6. The mutation affects a highly conserved amino acid residue in the Tubby domain, and is predicted to be pathogenic using several prediction programs. The mutation was not found in 159 ethnically matched controls, nor in our in-house exome (n=383) database and online exome and SNP databases. Screening of 159 cone dystrophy individuals identified the same mutation in an unrelated CD patient. Both patients carried the homozygous p.Arg420Ser mutation and displayed a cone dystrophy characterized by deterioration of visual acuity, a reduced cone ERG, and central sensitivity loss on perimetry.
Maternal UPD of chromosome 6 unmasked a mutation in the TULP1 gene as a novel cause of arCD. This expands the disease spectrum of TULP1 mutations from Leber congenital amaurosis and early-onset retinitis pigmentosa to cone-dominated disease.
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