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Isabelle Audo, Kinga Bujakowska, Elise Orhan, Florian Sennlaub, Xavier Guillonneau, Thierry Leveillard, Saddek Mohand-Said, Shomi Bhattacharya, Jose Sahel, Christina Zeitz; The familial dementia gene revisited: ITM2B missense mutation causes a new dominant retinal dystrophy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3356.
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© ARVO (1962-2015); The Authors (2016-present)
To identify and characterize the underlying genetic defect of an unusual autosomal dominant inherited retinal dystrophy comprising inner retinal dysfunction, ganglion cell abnormalities and progressive cone degeneration.
Phenotypic characterization and exclusion of known gene defect using Sanger and next generation sequencing had been previously presented (ARVO 2012, abstract # 1226). Whole exome sequencing was applied to two affected and one unaffected family members. Stringent filtering with the use of available SNP and retinal transcriptomic databases, co-segregation analysis and haplotyping using microsatellite markers were carried out to select the most likely pathogenic variant. Expression and immuno-localization studies were performed by RT-PCR, in situ hybridization and immunostainning on mouse and human retinal samples. In addition, subcellular localization of the wildtype and mutated protein was analyzed after COS-1 cell transient transfection.
Whole exome sequencing identified a new missense variant [c.782A>C, p.Glu261Ala], in ITM2B (Integral Membrane Protein 2B) which co-segregates with the disease in this large family. Subsequent haplotype analysis on chromosome 13q identified a crossover between markers D13S1272 and D13S275 leading to an interval of 24.6Mb including ITM2B, with the same haplotype present in all affected members available. ITM2B mRNA is highly expressed in the retina and localized in the inner nuclear and ganglion cell layer. Similarly, immuno-localization shows staining of the same layers. Functional assay does not show mutant protein membrane miss-localization.
This is the first report of a missense change in ITM2B associated with a peculiar autosomal dominant retinal restricted disease. Mutations in this gene have previously been reported in two distinct autosomal dominant Alzheimer-like dementia families. Pathogenic mechanism(s) that lead either to a restricted peculiar retinal phenotype or dementia in association with ITM2B mutations need to be further elucidated.
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