![]() ![]() Unlike other genetic backgrounds, the A/J background predisposes mice to age-related retinal degeneration 18, 19 which is a hallmark of many inherited blinding disorders. When placed in the A/J background, however, the RP1h tm1Eap allele induced severe age-dependent retinal degeneration. 17 When RP1h tm1Eap allele was placed in C57BL/6J or DBA1/J backgrounds, it did not induce apparent retinal degeneration phenotype. For example, effects of different genetic backgrounds were clearly illustrated by the study of retinitis pigmentosa 1 homolog (RP1h) mutant allele, RP1h tm1Eap. 1, 2, 15, 16 In mouse, studies of different genetic backgrounds were instructive to understand the effect of modifiers on the age-dependent deterioration of vision. Such genetic interaction is potentially one of the causes for variable onsets of hearing or vision loss observed in human USH patients. 11 – 14 Accordingly, interpretations of phenotypic outcomes tend to be complicated by the genetic interactions between USH causative genes and their modifiers. Severities of Mendelian diseases, including Usher syndrome (USH), are affected by other genes collectively called modifiers. 10 Currently, the role of CLRN1 in the retina is unknown, largely because there are no model animals that recapitulate the visual defects of USHIII. Furthermore, recent study using CLRN1-deficient zebrafish suggests that CLRN1 is also potentially involved in synaptic transmission by hair cells. 7 Consistently, studies of CLRN1-deficient mouse 7 – 9 and zebrafish 10 indicate structural and functional defects in the stereocilia: actin-filled membrane structures responsible for the mechanosensation of auditory hair cells. ![]() Proteomics analysis of CLRN1-interacting proteins suggests that CLRN1 is associated with the regulation of actin homeostasis. 5, 6 The gene is predicted to encode a four transmembrane domains protein (CLRN1) with unknown function. 2 – 4 Clarin-1 ( Clrn1) is currently the only gene associated with USHIII. For example, vision in the peripheral field is lost in the first 2 to 3 decades of life, and thereafter central vision can last for 1 or 2 more decades. 1, 2 Onsets of both hearing and vision loss are highly variable. Usher syndrome type III (USHIII) is characterized by progressive loss of hearing and vision as well as by variable degrees of balance disorder. Biallelic Clrn1 N48K/N48K mutations did not cause discernible visual defects, suggesting that Clrn1 − allele is more severely dysfunctional than Clrn N48K allele. The absence of apparent rod degeneration suggests that the observed phenotype is due to functional defects, and not due to loss of rods. Mutations that are Clrn1 −/− biallelic cause visual defects when placed under A/J background. In Clrn1 N48K/N48K mice, both a- and b-wave amplitudes were not discernable from those of wild type mice aged up to 10 months. ![]() Those electrophysiological defects were not associated with a loss of rods. Photopic ERG responses were comparable between Clrn1 −/− and wild type mice. In 9-month-old Clrn1 −/− mice, scotopic b-wave amplitudes were further reduced by more than 35%, and scotopic a-wave amplitude also showed a small decline as compared with wild type mice. s/m 2, but scotopic a-wave amplitudes were comparable to those of age-matched wild type mice at all the light intensities tested.In 3-month-old Clrn1 −/− mice, scotopic b-wave amplitude was reduced by more than 25% at the light intensities from −2.2 to 0.38 log cd To observe if there are any structural abnormalities, we conducted light and transmission electron microscopy of fixed retinal specimens. To study the retinal functions of these mice, we measured scotopic and photopic ERG responses. Speed congenic method was used to obtain Clrn1 exon 1 knockout ( Clrn1 −/−) and Clrn1 N48K knockin ( Clrn1 N48K/N4 8K) mice under A/J background. The purpose of this study was to obtain an Usher syndrome type III mouse model with retinal phenotype. ![]()
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