AIM：To investigate the relationship between high myopia [with or without complete congenital stationary night blindness（CSNB1）] and TRPM1 and NYX.METHODS： Two unrelated families with early-onset high myopia（eo HM...AIM：To investigate the relationship between high myopia [with or without complete congenital stationary night blindness（CSNB1）] and TRPM1 and NYX.METHODS： Two unrelated families with early-onset high myopia（eo HM） and 96 normal controls were recruited.Sanger sequencing or clone sequencing were used for mutation screening.Further analyses of the available family members and the 96 normal controls were subsequently conducted to obtain additional evidence of the pathogenicity of these variants.The initial diagnosis of the probands was eo HM.We performed a further comprehensive examination of the available family members after mutations were detected in TRPM1 or NYX. RESULTS： Two novel compound heterozygous mutations in TRPM1 were detected in the recruited families.The proband in family A with eo HM carried a c.2594 C 〉T missense mutation in exon 19 and a c.669 ＋3_669 ＋6del AAGT splicing mutation,which was co-segregated with CSNB1 in this family.A patient in family B with a compound heterozygous missense mutation（c.3262 G〉A and c.3250 T〉C） was detected.No mutations were found in NYX.These two identified compound heterozygous mutations were not found in the 96 normal controls.After further examination of the family members,the patients in family A could be diagnosed as eo HM with CSNB1.However due to the limited clinic data,the patient in family B cloud not clearly diagnosed as CSNB1.CONCLUSION： This study has expanded the mutation spectrum of TRPM1 for CSNB1 and additional studiesare needed to elucidate the association between isolated high myopia and TRPM1 and NYX.展开更多
Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells.Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity ...Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells.Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity with several genes mutated in patients affected by these genetic diseases.The high genetic heterogeneity of these diseases hampers the development of effective therapeutic interventions for the cure of a large cohort of patients.Common cell demise mechanisms can be envisioned as targets to treat patients regardless the specific mutation.One of these targets is the increase of intracellular calcium ions,that has been detected in several murine models of inherited retinal degeneration.Recently,neurotrophic factors that favor the efflux of calcium ions to concentrations below toxic levels have been identified as promising molecules that should be evaluated as new treatments for retinal degeneration.Here,we discuss therapeutic options for inherited retinal degeneration and we will focus on neuroprotective approaches,such as the neuroprotective activity of the Pigment epithelium-derived factor.The characterization of specific targets for neuroprotection opens new perspectives together with many questions that require deep analyses to take advantage of this knowledge and develop new therapeutic approaches.We believe that minimizing cell demise by neuroprotection may represent a promising treatment strategy for retinal degeneration.展开更多
Current rodent models of the complete congenital stationary night blindness (CSNB1) were time- consuming in breeding and validation, which makes it imperative to find a more “easily handle” animal model to broaden o...Current rodent models of the complete congenital stationary night blindness (CSNB1) were time- consuming in breeding and validation, which makes it imperative to find a more “easily handle” animal model to broaden our understanding of this disorder. In the present study, a light-deprivation (LD) mouse model was made to validate whether it was a more “suitable” animal mode for investigating the pathogenesis of the CSNB1. Compared with controls, the LD mice exhibited a remarkable reduction in the amplitude of the dark-adapted electroretinogram (ERG) b-wave, the Max-ERG b-wave and also the oscillatory potentials (Ops), indicating an abnormal activity of rod bipolar cells in the retina. However, the ERG a-wave was relatively normal in the LD mice, which was quite consistent with what was confirmed in previously reported animal models of the CSNB1 and CSNB patients. Taken together, the LD mouse model showed CSNB1-like negative ERG responses as evidenced by the abnormal b-wave. Our study will provide a potentially useful animal model to decipher the pathogenesis of the CSNB1.展开更多
基金Supported by the National Nature Science Foundation of China(No.81362138)
文摘AIM：To investigate the relationship between high myopia [with or without complete congenital stationary night blindness（CSNB1）] and TRPM1 and NYX.METHODS： Two unrelated families with early-onset high myopia（eo HM） and 96 normal controls were recruited.Sanger sequencing or clone sequencing were used for mutation screening.Further analyses of the available family members and the 96 normal controls were subsequently conducted to obtain additional evidence of the pathogenicity of these variants.The initial diagnosis of the probands was eo HM.We performed a further comprehensive examination of the available family members after mutations were detected in TRPM1 or NYX. RESULTS： Two novel compound heterozygous mutations in TRPM1 were detected in the recruited families.The proband in family A with eo HM carried a c.2594 C 〉T missense mutation in exon 19 and a c.669 ＋3_669 ＋6del AAGT splicing mutation,which was co-segregated with CSNB1 in this family.A patient in family B with a compound heterozygous missense mutation（c.3262 G〉A and c.3250 T〉C） was detected.No mutations were found in NYX.These two identified compound heterozygous mutations were not found in the 96 normal controls.After further examination of the family members,the patients in family A could be diagnosed as eo HM with CSNB1.However due to the limited clinic data,the patient in family B cloud not clearly diagnosed as CSNB1.CONCLUSION： This study has expanded the mutation spectrum of TRPM1 for CSNB1 and additional studiesare needed to elucidate the association between isolated high myopia and TRPM1 and NYX.
基金supported by grants from the Telethon Foundation(GGP14180,GGP19113)the European Union(LSHGCT-2005-512036 and transMed,MSCA-ITN-2017-765441)(all to VM)
文摘Inherited retinal degeneration is a major cause of incurable blindness characterized by loss of retinal photoreceptor cells.Inherited retinal degeneration is characterized by high genetic and phenotypic heterogeneity with several genes mutated in patients affected by these genetic diseases.The high genetic heterogeneity of these diseases hampers the development of effective therapeutic interventions for the cure of a large cohort of patients.Common cell demise mechanisms can be envisioned as targets to treat patients regardless the specific mutation.One of these targets is the increase of intracellular calcium ions,that has been detected in several murine models of inherited retinal degeneration.Recently,neurotrophic factors that favor the efflux of calcium ions to concentrations below toxic levels have been identified as promising molecules that should be evaluated as new treatments for retinal degeneration.Here,we discuss therapeutic options for inherited retinal degeneration and we will focus on neuroprotective approaches,such as the neuroprotective activity of the Pigment epithelium-derived factor.The characterization of specific targets for neuroprotection opens new perspectives together with many questions that require deep analyses to take advantage of this knowledge and develop new therapeutic approaches.We believe that minimizing cell demise by neuroprotection may represent a promising treatment strategy for retinal degeneration.
文摘Current rodent models of the complete congenital stationary night blindness (CSNB1) were time- consuming in breeding and validation, which makes it imperative to find a more “easily handle” animal model to broaden our understanding of this disorder. In the present study, a light-deprivation (LD) mouse model was made to validate whether it was a more “suitable” animal mode for investigating the pathogenesis of the CSNB1. Compared with controls, the LD mice exhibited a remarkable reduction in the amplitude of the dark-adapted electroretinogram (ERG) b-wave, the Max-ERG b-wave and also the oscillatory potentials (Ops), indicating an abnormal activity of rod bipolar cells in the retina. However, the ERG a-wave was relatively normal in the LD mice, which was quite consistent with what was confirmed in previously reported animal models of the CSNB1 and CSNB patients. Taken together, the LD mouse model showed CSNB1-like negative ERG responses as evidenced by the abnormal b-wave. Our study will provide a potentially useful animal model to decipher the pathogenesis of the CSNB1.
