Clinical manifestations of a unique X‐linked retinal disorder in a large New Zealand family with a novel mutation in CACNA1F, the gene responsible for CSNB2

Abstract

Although there were similarities to CSNB2, distinctive features in male family members included severity of phenotype, and association of intellectual disability. Moreover, all female heterozygotes had clinical and ERG abnormalities. CACNA1F encodes the Ca(v)1.4 alpha1 subunit of a voltage-gated calcium channel, which may mediate neurotransmitter release from photoreceptors. Molecular analyses, reported separately, identified a novel I745T CACNA1F mutation that was associated in vitro with major alterations in gating and kinetics of the Ca(v)1.4 channel. It is speculated that the unique phenotype described in this family may reflect similarly altered function of Ca(v)1.4 channel activity in vivo.

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

“…It is not clear if these functional abnormalities noted in the α 1F -KO mutant are stable across age. Nevertheless, these functional abnormalities appear to distinguish α 1F -KO mice from patients with CSNB2 and raise the possibility that the α 1F -KO mouse develops cone photoreceptor dysfunction or degeneration, a possibility discussed by Mansergh et al (2005) and consistent with recent reports linking some Cacna1f mutations with progressive retinal disorders (Nakamura et al, 2003;Jalkanen et al, 2004;Hope et al, 2005).…”

Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1

“…It will be important to see whether our results are confirmed in larger samples, for at least two reasons: on one hand, they suggest that the status of 'unaffected sibling' could define an individual possessing genetically determined compensatory mechanisms not available to autistic patients, rather than merely identifying family members who have not inherited the full array of disease-producing alleles. Our recent identification of another protective variant in the glyoxalase I gene, 35 in conjunction with gain-of-function mutations in the CACNA1F gene consistently yielding night blindness while causing autism or epilepsy only in a subset of carriers, 44 provide converging evidence of genetic backgrounds effectively protecting from autism. On the other hand, our results would provide further support for key contributions of Ca 2 þ -triggered AGC1 activity to autism pathogenesis.…”

“…43 Similarly, mutations in the L-type voltage-gated Ca 2 þ channel Ca v 1.4 (CACNA1F) cause the incomplete form of X-linked congenital stationary night blindness (CSNB2): gain-of-function mutations cause CSNB2 frequently accompanied by cognitive impairment and either autism or epilepsy, whereas CSNB2 due to lossof-function mutations is not accompanied by these symptoms. 44 All of these gain-of-function mutations prevent voltage-dependent channel inactivation leading to excessive Ca 2 þ influx. Also mutations indirectly yielding increased cytosolic Ca 2 þ levels or amplifying intracellular Ca 2 þ signaling by hampering Ca 2 þ -activated negative feedback mechanisms have been found associated with autism.…”

ACACNA1Fmutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation

“…Clinical investigations have recently characterized an X-linked retinal disorder that is similar to, but distinct from, CSNB2 in a New Zealand family (13). Male individuals had congenital nystagmus, severe nonprogressive impairment of visual acuity, frequent hypermetropia, and normal fundi.…”