Mutations in theCACNA1F andNYX genes in British CSNBX families

Abstract

Communicated by Jean-Louis MandelX-linked congenital stationary night blindness (CSNBX) is a genetically and phenotypically heterogeneous non-progressive disorder, characterised by impaired night vision but grossly normal retinal appearance. Other more variable features include reduction in visual acuity, myopia, nystagmus and strabismus. Genetic mapping studies by other groups, and our own studies of British patients, identified key recombination events indicating the presence of at least 2 disease genes on Xp11. Two causative genes (CACNA1F and NYX) for CSNBX have now been identified through positional cloning strategies. In this report, we present the results of comprehensive mutation screening in 14 CSNBX families, three with mutations in the CACNA1F gene and 10 with mutations in the NYX gene. In one family we failed to identify the mutation after testing RP2, RPGR, NYX and CACNA1F. NYX gene mutations are a more frequent cause of CSNBX, although there is evidence for founder mutations. Our report of patient population mutation screening for both CSNBX genes, and our exclusion of RP2 and RGPR, indicates that mutations in CACNA1F and NYX are likely to account for all CSNBX.

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

“…Mutations in CSNB2 patients that encode early truncations in CACNA1F (35,36) are likely to represent null alleles. Because CSNB2 patients retain moderate vision despite loss of Ca v 1.4 channel activity, it has been suggested that other classes of L-type calcium channels may continue to permit some lightdependent modulation of glutamate release (10).…”

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].…”

A common variant in combination with a nonsense mutation in a member of the thioredoxin family causes primary ciliary dyskinesia

“…Previous studies suggested that alteration of this structure may result from intraflagellar transport dysfunction and lead to retinal degeneration (47)(48)(49)(50). Noteworthy, a link has been established between photoreceptor and respiratory cilia with the identification of mutations in RPGR, which encodes a GTPase regulator involved in X-linked RP, in families presenting with a complex disease phenotype combining RP with various defects of respiratory cilia and even PCD (24,51,52).…”