Anterior chamber depth in mice is controlled by several quantitative trait loci.

Anterior chamber depth (ACD) is a quantitative trait associated with primary angle closure glaucoma (PACG). Although ACD is highly heritable, known genetic variations explain a small fraction of the phenotypic variability. The purpose of this study was to identify additional ACD-influencing loci using strains of mice. Cohorts of 86 N2 and 111 F2 mice were generated from crosses between recombinant inbred BXD24/TyJ and wild-derived CAST/EiJ mice. Using anterior chamber optical coherence tomography, mice were phenotyped at 10-12 weeks of age, genotyped based on 93 genome-wide SNPs, and subjected to quantitative trait locus (QTL) analysis. In an analysis of ACD among all mice, six loci passed the significance threshold of p = 0.05 and persisted after multiple regression analysis. These were on chromosomes 6, 7, 11, 12, 15 and 17 (named Acdq6, Acdq7, Acdq11, Acdq12, Acdq15, and Acdq17, respectively). Our findings demonstrate a quantitative multi-genic pattern of ACD inheritance in mice and identify six previously unrecognized ACD-influencing loci. We have taken a unique approach to studying the anterior chamber depth phenotype by using mice as genetic tool to examine this continuously distributed trait.

The Efemp1R345W Macular Dystrophy Mutation Causes Amplified Circadian and Photophobic Responses to Light in Mice.

Purpose: The R345W mutation in EFEMP1 causes malattia leventinese, an autosomal dominant eye disease with pathogenesis similar to an early-onset age-related macular degeneration. In mice, Efemp1R345W does not cause detectable degeneration but small subretinal deposits do accumulate. The purpose of this study was to determine whether there were abnormal responses to light at this presymptomatic stage in Efemp1R345W mice. Methods: Responses to light were assessed by visual water task, circadian phase shifting, and negative masking behavior. The mechanism of abnormal responses was investigated by anterior eye exam, electroretinogram, melanopsin cell quantification, and multielectrode recording of retinal ganglion cell activity. Results: Visual acuity was not different in Efemp1R345W mice. However, amplitudes of circadian phase shifting (P = 0.016) and negative masking (P < 0.0001) were increased in Efemp1R345W mice. This phenotype was not explained by anterior eye defects or amplified outer retina responses. Instead, we identified increased melanopsin-generated responses to light in the ganglion cell layer of the retina (P < 0.01). Conclusions: Efemp1R345W increases the sensitivity to light of behavioral responses driven by detection of irradiance. An amplified response to light in melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) is consistent with this phenotype. The major concern with this effect of the malattia leventinese mutation is the potential for abnormal regulation of physiology by light to negatively affect health.

Mouse models and strain-dependency of Chédiak-Higashi syndrome-associated neurologic dysfunction.

Chédiak-Higashi syndrome (CHS) is a lethal disorder caused by mutations in the LYST gene that involves progressive neurologic dysfunction. Lyst-mutant mice exhibit neurologic phenotypes that are sensitive to genetic background. On the DBA/2J-, but not on the C57BL/6J-background, Lyst-mutant mice exhibit overt tremor phenotypes associated with loss of cerebellar Purkinje cells. Here, we tested whether assays for ataxia could measure this observed strain-dependency, and if so, establish parameters for empowering phenotype- and candidate-driven approaches to identify genetic modifier(s). A composite phenotypic scoring system distinguished phenotypes in Lyst-mutants and uncovered a previously unrecognized background difference between wild-type C57BL/6J and DBA/2J mice. Accelerating rotarod performance also distinguished phenotypes in Lyst-mutants, but at more advanced ages. These results establish that genetic background, Lyst genotype, and age significantly influence the severity of CHS-associated neurologic deficits. Purkinje cell quantifications likewise distinguished phenotypes of Lyst-mutant mice, as well as background differences between wild-type C57BL/6J and DBA/2J mice. To aid identification of potential genetic modifier genes causing these effects, we searched public datasets for cerebellar-expressed genes that are differentially expressed and/or contain potentially detrimental genetic variants. From these approaches, Nos1, Prdx2, Cbln3, Gnb1, Pttg1 were confirmed to be differentially expressed and leading candidates.