Spontaneous allelic variant in deafness–blindness gene Ush1g resulting in an expanded phenotype

Authors

Vladimir Vartanian, Oregon Health & Science University
Jocelyn F. Krey, Oregon Health & Science University
Paroma Chatterjee, Oregon Health & Science University
Allison Curtis, Oregon Health & Science University
Makayla Six, Oregon Health & Science University
Sean P. M. Rice, Oregon Health & Science University-Portland State University
Sherri M. Jones, University of Nebraska-LincolnFollow
Harini Sampath, Rutgers University
Charles N. Allen, Oregon Health & Science University
Renee C. Ryals, Oregon Health & Science University
R. Stephen Lloyd, Oregon Health & Science University
Peter G. Barr-Gillespie, Oregon Health & Science University

Document Type

Article

Date of this Version

5-7-2023

Citation

Vartanian V, Krey JF, Chatterjee P, et al. Spontaneous allelic variant in deafness–blindness gene Ush1g resulting in an expanded phenotype. Genes, Brain and Behavior. 2023;e12849. doi:10.1111/gbb.12849

Comments

Open access.

Abstract

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/bwnull 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.