title: Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness.
abstract: 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 alpha 1-subunit of an L-type Ca2+ channel (Cav1.4 alpha ), 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 Cav1.4 alpha . Mice lacking either Cabp4 or Cav1.4 alpha 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.
authors.affiliation: Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland. zeitz@medgen.unizh.ch
authors.forename: Christina
authors.initials: C
authors.lastname: Zeitz
authors.forename: Barbara
authors.initials: B
authors.lastname: Kloeckener-Gruissem
authors.forename: Ursula
authors.initials: U
authors.lastname: Forster
authors.forename: Susanne
authors.initials: S
authors.lastname: Kohl
authors.forename: István
authors.initials: I
authors.lastname: Magyar
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Gábor
authors.initials: G
authors.lastname: Mátyás
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Borruat
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.forename: Francis L
authors.initials: FL
authors.lastname: Munier
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D020746:Calcium Channels, L-Type / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D004596:Electroretinography; D005091:Exons; D005260:Female; D017353:Gene Deletion; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009755:Night Blindness / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D014792:Visual Acuity
chemical_list: C514441:CABP4 protein, human; C113330:CACNA1F protein, human; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins