A Novel Large In-Frame Deletion within the CACNA1F Gene Associates with a Cone-Rod Dystrophy 3-Like Phenotype

Abstract

Cone-rod dystrophies (CORDs) represent a heterogeneous group of monogenic diseases leading to early impairment of vision. The majority of CORD entities show autosomal modes of inheritance and X-linked traits are comparably rare. So far, three X-chromosomal entities were reported (CORDX1, -X2 and -X3). In this study, we analysed a large family of German origin with solely affected males over three generations showing a CORDX-like phenotype. Due to the heterogeneity of cone-rod dystrophies, we performed a combined linkage and X-exome sequencing approach and identified a novel large intragenic in-frame deletion encompassing exons 18 to 26 within the CACNA1F gene. CACNA1F is described causative for CORDX3 in a single family originating from Finland and alterations in this gene have not yet been reported in other CORDX pedigrees. Our data independently confirm CACNA1F as the causative gene for CORDX3-like phenotypes and detailed clinical characterization of the family expands the knowledge about the phenotypic spectrum of deleterious CACNA1F alterations.

Congenital stationary night blindness: An analysis and update of genotype–phenotype correlations and pathogenic mechanisms

“…This distinction between icCSNB and cone dystrophy is however sometimes difficult. Some reports have shown possible progression of visual dysfunction in this subgroup with icCSNB gene defects associated with retinal degeneration (Aldahmesh et al, 2010;Hauke et al, 2013;Huang et al, 2013;Jalkanen et al, 2006;Nakamura et al, 2003a.…”

“…Although this is different in patients with typical icCSNB, a similar but more severe phenotype has been reported in a large family in association with p.Ile745Thr exchange in CACNA1F; there was severe non-progressive visual impairment with intellectual disability in some . Both Cacna1f knockout mouse models show functional blindness and could be better described as models for cone-rod dystrophy (Knoflach et al, 2013;Mansergh et al, 2005;Michalakis et al, 2014) and it is noted that patients with X-linked coneerod dystrophy type 3 show mutations in CACNA1F Hauke et al, 2013;Huang et al, 2013;Jalkanen et al, 2006). Further studies are needed to clarify differences between mouse and humans in terms of genetic background, genetic modifiers, or the type of CACNA1F mutation that may influence the phenotype Boycott et al, 2000;Hope et al, 2005;Jalkanen et al, 2007Jalkanen et al, , 2006Strom et al, 1998;Vincent et al, 2011).…”

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

“…Furthermore, a hemizygous mutation in the CACNA1F gene (p.R1060W) was discovered in proband H29. CACNA1F mutations are reported in patients with HM, congenital stationary night blindness type 2A (43), cone-rod dystrophy (44), and nyctalopia (45).…”

Establishment and rapid detection of a heterozygous missense mutation in the CACNA1F gene by ARMS technique with double-base mismatched primers

“…Mutations in CACNA1F are mostly associated with incomplete X-linked congenital stationary night blindness type 2A (CSNB2A) (Hauke et al, 2013). According to the Human Gene Mutation Database, more than 60 different CACNA1F mutations have been reported to cause CSNB2A.…”

“…300110) encodes a voltage-dependent L-type calcium channel, the Ca v 1.4 channel. It is expressed in both rod and cone terminals mediating neurotransmitter secretion at ribbon synapses of the retinal photoreceptors, and therefore plays an important role in signal transmission from photoreceptors to bipolar cells in the retinal neurons (Baumann et al, 2004;Hauke et al, 2013). Mutations in the CACNA1F gene are associated with some progressive retinal disorder with a large phenotypic variability .…”