A missense mutation of Ip3r1 in Dp2 mice leads to short-term mydriasis and unfolded protein response in the iris constrictor muscles

Abstract

ABSTRACTIp3r1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. Mutations in the Ip3r1 gene in humans may cause Gillespie syndrome (GS) typically presents as fixed dilated pupils in affected infants, which was referred to as iris hypoplasia. However, there is no report of mice with Ip3r1 heterozygous mutations showing dilated pupils. Here, we report a new Ip3r1 allele (dilated pupil 2; Dp2) with short-term dilated pupil phenotype derived from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. This allele carries a G5927A transition mutation, which is predicted to result in a C1976Y amino acid change in the open reading frame. Histology and pharmacological tests show that the dilated pupil phenotype is a mydriasis caused by the functional defect in the iris constrictor muscles in Dp2. The dilated pupil phenotype in Dp2 was referred to as mydriasis and excluding iris hypoplasia. IHC analysis revealed increased expression of BIP protein, the master regulator of unfolded protein response (UPR) signaling, in Dp2 mice that did not recover. Apart from the dilated pupil phenotype (mydriasis), there are no other abnormal phenotypes including Ip3r1-related ataxia that may be found. This study is the first report of an Ip3r1 mutation being associated with the mydriasis phenotype. Dp2 mice represent a valuable self-healing model that may be used to study the therapeutic approach for Ip3r1-related diseases or diseases caused by similar pathomechanisms.