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Silvio Alessandro Di Gioia, Giulia Venturini, Shyana Harper, Eliot L. Berson, Carlo Rivolta; Mutation Screening Of The FAM161A Gene (RP28) In An Autosomal Recessive Retinitis Pigmentosa Cohort. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5371.
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© ARVO (1962-2015); The Authors (2016-present)
Following the molecular analysis of a consanguineous Indian family, we have recently identified FAM161A as the gene that is responsible for autosomal recessive retinitis pigmentosa (arRP) linked to the RP28 locus. Mutations in this gene were also present in patients with arRP in Europe and, with relatively high prevalence, in Israel. To better understand the contribution of FAM161A to the disease and to identify new pathological variants, we have screened its DNA sequence in an extended cohort of 192 unrelated patients with arRP from North America.
All 7 annotated exons and relevant intron boundaries defining the gene were amplified by PCR and sequenced by capillary electrophoresis. The DNA samples analyzed were from patients who were negative for mutations in most other arRP genes. Assessment of nonsense-mediated mRNA decay (NMD) was performed by RT-PCR on transcripts from lymphoblastoid cell lines derived from patients.
In addition to a number of presumably benign variants, we identified the previously known p.T452Sfx3 mutation homozygously in 2 unrelated individuals. Another patient was a compound heterozygote for two new missense variations (p.L478R/p.R562W) within exon 3 and the alternative spliced exon 3a, respectively. All of these variants were absent in 350 control chromosomes. The p.T452Sfx3 frameshift is predicted in silico to generate mRNA that is a target for NMD, leading to mRNA degradation and no or reduced protein product. Preliminary data on lymphoblasts support this hypothesis, although validation experiments are still pending.
We ascertained that mutations in FAM161A are a cause of arRP in North America, with an estimated prevalence of at least 2% among all recessive cases. This frequency is similar to that of many other arRP genes. If confirmed, data on NMD suggest that FAM161A mutations cause RP by a loss-of-function mechanism.
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