title: Mosaic synaptopathy and functional defects in Cav1.4 heterozygous mice and human carriers of CSNB2.
abstract: Mutations in CACNA1F encoding the α1-subunit of the retinal Cav1.4 L-type calcium channel have been linked to Cav1.4 channelopathies including incomplete congenital stationary night blindness type 2A (CSNB2), Åland Island eye disease (AIED) and cone-rod dystrophy type 3 (CORDX3). Since CACNA1F is located on the X chromosome, Cav1.4 channelopathies are typically affecting male patients via X-chromosomal recessive inheritance. Occasionally, clinical symptoms have been observed in female carriers, too. It is currently unknown how these mutations lead to symptoms in carriers and how the retinal network in these females is affected. To investigate these clinically important issues, we compared retinal phenotypes in Cav1.4-deficient and Cav1.4 heterozygous mice and in human female carrier patients. Heterozygous Cacna1f carrier mice have a retinal mosaic consistent with differential X-chromosomal inactivation, characterized by adjacent vertical columns of affected and non-affected wild-type-like retinal network. Vertical columns in heterozygous mice are well comparable to either the wild-type retinal network of normal mice or to the retina of homozygous mice. Affected retinal columns display pronounced rod and cone photoreceptor synaptopathy and cone degeneration. These changes lead to vastly impaired vision-guided navigation under dark and normal light conditions and reduced retinal electroretinography (ERG) responses in Cacna1f carrier mice. Similar abnormal ERG responses were found in five human CACNA1F carriers, four of which had novel mutations. In conclusion, our data on Cav1.4 deficient mice and human female carriers of mutations in CACNA1F are consistent with a phenotype of mosaic CSNB2.
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM) and Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.forename: Lior
authors.initials: L
authors.lastname: Shaltiel
authors.forename: Vithiyanjali
authors.initials: V
authors.lastname: Sothilingam
authors.forename: Susanne
authors.initials: S
authors.lastname: Koch
authors.forename: Verena
authors.initials: V
authors.lastname: Schludi
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krause
authors.forename: Christina
authors.initials: C
authors.lastname: Zeitz
authors.forename: Isabelle
authors.initials: I
authors.lastname: Audo
authors.forename: Marie-Elise
authors.initials: ME
authors.lastname: Lancelot
authors.forename: Christian
authors.initials: C
authors.lastname: Hamel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
authors.forename: Markus N
authors.initials: MN
authors.lastname: Preising
authors.forename: Christoph
authors.initials: C
authors.lastname: Friedburg
authors.forename: Birgit
authors.initials: B
authors.lastname: Lorenz
authors.forename: Nawal
authors.initials: N
authors.lastname: Zabouri
authors.forename: Silke
authors.initials: S
authors.lastname: Haverkamp
authors.forename: Marina
authors.initials: M
authors.lastname: Garcia Garrido
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tanimoto
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Christian A
authors.initials: CA
authors.lastname: Wahl-Schott
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004596:Electroretinography; D015785:Eye Diseases, Hereditary / Q000235:genetics / Q000473:pathology*; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009216:Myopia / Q000235:genetics / Q000473:pathology*; D009755:Night Blindness / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D014960:X Chromosome; D049951:X Chromosome Inactivation
chemical_list: C113330:CACNA1F protein, human; C480684:Cacna1f protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type