Spontaneous allelic variant in deafness-blindness gene Ush1g resulting in an expanded phenotype.
Vladimir VartanianJocelyn F KreyParoma ChatterjeeAllison CurtisMakayla SixSean P M RiceSherri M JonesHarini SampathCharles N AllenRenee C RyalsR Stephen LloydPeter G Barr-GillespiePublished in: Genes, brain, and behavior (2023)
Relationships between novel phenotypic behaviors and specific genetic alterations are often discovered using target-specific, directed mutagenesis or phenotypic selection following chemical mutagenesis. An alternative approach is to exploit deficiencies in DNA repair pathways that maintain genetic integrity in response to spontaneously induced damage. Mice deficient in the DNA glycosylase NEIL1 show elevated spontaneous mutations, which arise from translesion DNA synthesis past oxidatively induced base damage. Several litters of Neil1 knockout mice included animals that were distinguished by their backwards-walking behavior in open-field environments, while maintaining frantic forward movements in their home cage environment. Other phenotypic manifestations included swim test failures, head tilting and circling. Mapping of the mutation that conferred these behaviors showed the introduction of a stop codon at amino acid 4 of the Ush1g gene. Ush1g bw/bw null mice displayed auditory and vestibular defects that are commonly seen with mutations affecting inner-ear hair-cell function, including a complete lack of auditory brainstem responses and vestibular-evoked potentials. As in other Usher syndrome type I mutant mouse lines, hair cell phenotypes included disorganized and split hair bundles, as well as altered distribution of proteins for stereocilia that localize to the tips of row 1 or row 2. Disruption to the bundle and kinocilium displacement suggested that USH1G is essential for forming the hair cell's kinocilial links. Consistent with other Usher type 1 models, Ush1g bw/bw mice had no substantial retinal degeneration compared with Ush1g bw /+ controls. In contrast to previously described Ush1g alleles, this new allele provides the first knockout model for this gene.
Keyphrases
- dna repair
- genome wide
- copy number
- wild type
- high fat diet induced
- dna damage
- high glucose
- crispr cas
- oxidative stress
- single cell
- diabetic rats
- amino acid
- hearing loss
- cell therapy
- single molecule
- genome wide identification
- mesenchymal stem cells
- working memory
- magnetic resonance
- high resolution
- optic nerve
- drug induced
- type diabetes
- diabetic retinopathy
- gene expression
- skeletal muscle
- stem cells
- transcription factor
- endothelial cells
- contrast enhanced
- adipose tissue
- case report
- high density