Thirty distinct CACNA1F mutations in 33 families with incomplete type of XLCSNB and Cacna1f expression profiling in mouse retina

Abstract

X-linked CSNB patients may exhibit myopia, nystagmus, strabismus and ERG abnormalities of the Schubert-Bornschein type. We recently identified the retina-specific L-type calcium channel a1 subunit gene CACNA1F localised to the Xp11.23 region, which is mutated in families showing the incomplete type (CSNB2). Here, we report comprehensive mutation analyses in the 48 CACNA1F exons in 36 families, most of them from Germany. All families were initially diagnosed as having the incomplete type of CSNB, except for two which have been designated as Å land Island eye disease (Å IED)-like. Out of 33 families, a total of 30 different mutations were identified, of which 24 appear to be unique for the German population. The mutations, 20 of which are published here for the first time, were found to be equally distributed over the entire gene sequence. No mutation could be found in a classic Å IED family previously shown to map to the CSNB2 interval. Cacna1f expression in photoreceptor-negative mice strains indicate that the gene is expressed in the outer nuclear, the inner nuclear, and the ganglion cell layer. Such a distribution points to the central role of calcium regulation in the interaction of retinal cells that mediate signal transmission.

Night blindness-associated mutations in the ligand-binding, cysteine-rich, and intracellular domains of the metabotropic glutamate receptor 6 abolish protein trafficking

“…However, most of the CSNB cases described so far are associated with mutations in the two X-linked genes CACNA1F and NYX [Bech-Hansen et al, 1998Strom et al, 1998;Pusch et al, 2000;Nakamura et al, 2001;Boycott et al, 2001;Wutz et al, 2002;Zito et al, 2003;Allen et al, 2003;Jacobi et al, 2003;Zeitz et al, 2005a]. Recently, we and others showed that mutations in the GRM6 gene (MIM] 604096), encoding the human mGluR6, lead to autosomal recessive congenital stationary night blindness (arCSNB) [Dryja et al, 2005;Zeitz et al, 2005b].…”

Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

“…The incomplete form, CSNB2, is caused by mutations in the Cacna1f gene, encoding the α 1F subunit of VDCCs (Bech-Hansen et al, 1998;Strom et al, 1998;Boycott et al, 2001;Wutz et al, 2002). In the outer retina, expression of the α 1F subunit has been localized to the OPL where it is concentrated on the presynaptic side in the terminals of the photoreceptors at their "active zones," which are specialized to mediate continuous calcium-dependent neurotransmitter release (Morgans et al, 2001).…”

Characterization of Cav1.4 Complexes (α11.4, β2, and α2δ4) in HEK293T Cells and in the Retina

“…In mice, inactivation of CACNA1F, the gene encoding Ca v 1.4 (Ca v 1.4 KO), disrupts photoreceptor synaptic transmission and presynaptic calcium signaling (15) and prevents the maturation of photoreceptor synapses (13,16). In addition, human mutations in CACNA1F cause vision disorders, including incomplete congenital stationary night blindness 2, which is characterized by impaired rod photoreceptor transmission and low visual acuity in darkness (17)(18)(19)(20). Antibody labeling for the Ca v 1.3 ␣ 1 subunit has also been detected in the cones from tree shrew (21,22) and chick (23).…”