Mutations in CABP4, the Gene Encoding the Ca(2+)-Binding Protein 4, Cause Autosomal Recessive Night Blindness

Mutations in genes encoding either components of the phototransduction cascade or proteins presumably involved in signaling from photoreceptors to adjacent second-order neurons have been shown to cause congenital stationary night blindness (CSNB). Sequence alterations in CACNA1F lead to the incomplete type of CSNB (CSNB2), which can be distinguished by standard electroretinography (ERG). CSNB2 is associated with a reduced rod b-wave, a substantially reduced cone a-wave, and a reduced 30-Hz flicker ERG response. CACNA1F encodes the α(1)-subunit of an L-type Ca(2+) channel (Cav1.4α), which is specific to photoreceptors and is present at high density in the synaptic terminals. Ten of our patients with CSNB2 showed no mutation in CACNA1F. To identify the disease-causing mutations, we used a candidate-gene approach. CABP4, a member of the calcium-binding protein (CABP) family, is located in photoreceptor synaptic terminals and is directly associated with the C-terminal domain of the Cav1.4α. Mice lacking either Cabp4 or Cav1.4α display a CSNB2-like phenotype. Here, we report for the first time that mutations in CABP4 lead to autosomal recessive CSNB. Our studies revealed homozygous and compound heterozygous mutations in two families. We also show that these mutations reduce the transcript levels to 30%–40% of those in controls. This suggests that the reduced amount of CABP4 is the reason for the signaling defect in these patients

TRPM1 Is Mutated in Patients with Autosomal-Recessive Complete Congenital Stationary Night Blindness

Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX and GRM6, expressed in ON bipolar cells, lead to a disruption of the ON bipolar cell response. This dysfunction is present in patients with complete X-linked and autosomal-recessive congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete CSNB (cCSNB) are caused by mutations in NYX and GRM6, in ∼60% of the patients the gene defect remains unknown. Animal models of human diseases are a good source for candidate genes, and we noted that a cCSNB phenotype present in homozygous Appaloosa horses is associated with downregulation of TRPM1. TRPM1, belonging to the family of transient receptor potential channels, is expressed in ON bipolar cells and therefore qualifies as an excellent candidate. Indeed, mutation analysis of 38 patients with CSNB identified ten unrelated cCSNB patients with 14 different mutations in this gene. The mutation spectrum comprises missense, splice-site, deletion, and nonsense mutations. We propose that the cCSNB phenotype in these patients is due to the absence of functional TRPM1 in retinal ON bipolar cells

A spatial assessment of ecosystem services in Europe: methods, case studies and policy analysis - phase 2 synthesis report

Mainstreaming ecosystem services in EU decision making processes requires a solid conceptual and methodological framework for mapping and assessing ecosystem services that serve the multiple objectives addressed by policies. The PRESS-2 study (PEER Research on EcoSystem Services – Phase 2) provides such an analytical framework which enables the operationalization of the present scientific knowledge base of environmental data and models for application by the EU and Member States for mapping and assessment of ecosystem services. This study is structured along three strands of work: policy and scenario analysis, mapping and valuation. Linking maps of ecosystem services supply to monetary valuation allows an analysis of the expected impact of policy measures on benefits derived from ecosystem services

A spatial assessment of ecosystem services in Europe: methods, case studies and policy analysis - phase 2 [full report]

Mainstreaming ecosystem services in EU decision making processes requires a solid conceptual and methodological framework for mapping and assessing ecosystem services that serve the multiple objectives addressed by policies. The PRESS-2 study (PEER Research on EcoSystem Services – Phase 2) provides such an analytical framework which enables the operationalization of the present scientific knowledge base of environmental data and models for application by the EU and Member States for mapping and assessment of ecosystem services. This study is structured along three strands of work: policy and scenario analysis, mapping and valuation. Linking maps of ecosystem services supply to monetary valuation allows an analysis of the expected impact of policy measures on benefits derived from ecosystem services

PRESS - PEER Research on Ecosystem Services - A spatial assessment of ecosystem services in Europe - the Phase II Report - Synthesis

Mainstreaming ecosystem services in EU decision making processes requires a solid conceptual and methodological framework for mapping and assessing ecosystem services that serve the multiple objectives addressed by policies. The PRESS-2 study (PEER Research on Ecosystem Service – Phase 2) provides such an analytical framework which enables the operationalization of the present scientific knowledge base of environmental data and models for application by the EU and Member States for mapping and assessment of ecosystem services. This study is structured along three strands of work: policy and scenario analysis, mapping and valuation. Linking maps of ecosystem service supply to monetary valuation allows an analysis of the expected impact of policy measures on benefits derived from ecosystem services.JRC.H-Institute for Environment and Sustainability (Ispra

CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia.

Contains fulltext : 47591.pdf (publisher's version ) (Closed access)Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (<0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders

International audienceInherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.</p

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.status: publishe