A novel homozygous Tub mutation associated with autosomal recessive retinitis pigmentosa in a consanguineous Chinese family

Abstract Background: Retinitis pigmentosa (RP) is the most common type of inherited retinopathy with at least 69 genes identified thus far. A significant proportion of RP, However, remains genetically unsolved. In this study, the the genetic basis of a Chinese consanguineous family with autosomal recessive retinitis pigmentosa (arRP) was investigated. Methods : Overall ophthalmic examinations, including funduscopy, decimal best-corrected visual acuity (BCVA), axial length and electroretinography (ERG) were performed to confirm the diagnosis of the patients. Genomic DNA from peripheral blood of the proband was subjected to whole exome sequencing (WES). In silico predictions, structural modelling and minigene assays were conducted to evaluate the pathogenicity of the mutant. Results : Four candidate variants, including heterozygous variant in RAX2, RP1 and PITPNM3 and a homozygous variant in Tub , were detected as suspected pathegenic variants. The novel c.1379A > G mutation in Tub , based on sanger sequencing, was remained to be the only candidate variant that co-segregated with RP phenotype in this pedigree. More importantly, the Asn residue at codon 460 of TUB is highly conserved across diverse species from tropicalis to humans. And the homozygous c.1379A > G mutation in Tub was excluded from 118 ethnically matched normal controls. Although minigen assay revealed that this variant of c.1379A>G in Tub did not affect normal splicing in vitro, multiple bioinformatic algorithm predicted that this variant was deleterious. Conclusions : For the first time we reported the identification of a rare homozygous mutant ( c.1379A>G: p.N460S) in Tub in a consanguineous family with arRP, which was probably the pathogenic basis of arRP in this consanguineous family.