Novel compound heterozygous nonsense variants, p.L150* and p.Y3565*, of the USH2A gene in a Chinese pedigree are associated with Usher syndrome type�IIA

Abstract

usher syndrome refers to a group of genetically and clinically heterogeneous autosomal recessive diseases with retinitis pigmentosa (RP) and hearing deficiencies. The association between usher syndrome-causative genes and resultant Usher syndrome phenotypes in patients are highly variable. In the present study, a chinese family with usher syndrome was recruited, and targeted next-generation sequencing, Sanger sequencing and segregation analysis were performed. The expression profiles and functional effects of the pathogenic variants of USH2A identified were analyzed. Novel nonsense compound heterozygous variants, c.T449G (p.L150*) and c.T10695A (p.Y3565*), were identified in the USH2A gene, which showed co-segregation with the disease phenotype causing usher syndrome type iia in the recruited chinese pedigree. The p.L150* variant was predicted to produce a truncated protein which lacked almost all the functional domains of USH2A, whereas the p.Y3565* variant is located in one of the fibronectin type 3 domains, resulting in the loss of several fibronectin type 3 domains at the C-terminus of USH2A by producing the truncated protein. It was shown that Ush2a mrna expression levels were higher in the retina compared with those in the eye tissues (lens, sclera and cornea), uterus, ovary, breast, testis, spleen, kidney, liver, intestine, brain, skeletal muscle and blood. Additionally, the protein structure was shown to be highly conserved by comparing Homo sapiens USH2A to eight other species. To the best of our knowledge, the present study is the first to identify two novel pathogenic variants, c.T449G (p.L150*) and c.T10695A (p.Y3565*), in the USH2A gene in a patient with usher syndrome type iia, thereby expanding the known spectrums of USH2A causative mutations. The present discovery may assist in understanding the molecular pathogenesis underlying the development of rP and usher syndrome type iia, and in the development of diagnostic, therapeutic and genetic counseling strategies in patients with Usher syndrome type IIA disease.

Rare variant analyses across multiethnic cohorts identify novel genes for refractive error

“…USH2A is well known to cause both Usher syndrome, which includes retinitis pigmentosa (RP) and mild to moderate hearing loss, as well as RP without hearing loss 52 . It is known to be expressed in the retina 53 and has been recently shown to be associated with high myopia 54 Pathway and expression analysis on top prioritized genes. We ran the IPA and FUMA analyses on the seven top prioritized genes.…”

“…P4HTM affects eye morphology in mice knockouts; 55 it is also notable for being replicated in the UKBB analysis. USH2A is expressed in the retina and is a known RP gene 52 , 53 .…”

Novel compound heterozygous variants in the USH2A gene associated with autosomal recessive retinitis pigmentosa without hearing loss

“…The USH2A plays an essential role in the homeostasis, development, and function of visual and auditory sensory ( Molina-Ramírez et al, 2020 ; Toms et al, 2020 ). The protein includes three regions: i) a large extracellular region with a signal peptide, a laminin N-terminal, 10 laminin epidermal growth factor-like domains, and 34 fibronectin type-III domains separated by 2 laminin G-like domains; ii) a transmembrane region; iii) a short intracellular region with a PDZ-binding motif at its C-terminal end ( Liu et al, 2007 ; Chen et al, 2014 ; Fu et al, 2020 ; Zhu et al, 2021 ). The USH2A variants, including missense, nonsense, duplications/insertions, deletions, indels, and splicing variants, spread throughout the 72 exons and their flanking intronic regions ( Aller et al, 2006 ; Koyanagi et al, 2020 ; Gao et al, 2021 ).…”