Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-02-01
2003-12-30
Kemmerer, Elizabeth (Department: 1646)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S006120, C435S007200, C435S007210, C435S069100, C435S252300, C435S320100, C435S325000, C436S501000, C530S350000, C514S002600
Reexamination Certificate
active
06670465
ABSTRACT:
FIELD OF THE INVENTION
This present invention relates to calcium channel compositions. In particular, this invention relates to a mammalian gene encoding a retinal calcium channel subunit polypeptide, herein referred to as CACNA1F, wherein mutations of CACNA1F may cause a type of X-linked congenital stationary night blindness.
REFERENCES
The following references are cited in the application as numbers in brackets ([ ]) at the relevant portion of the application. Each of these references is incorporated herein by reference.
1. Héon and Musarella, “Congenital stationary night blindness: a critical review for molecular approaches”, in
Molecular Genetics of Inherited Eye Disorders
(eds. Wright, A. F. & Jay, B.) pp 277-301 (Harwood Academic Publishers, London, 1994).
2. Miyake, et al., “Congenital stationary night blindness with negative electroretinogram”,
Arch. Ophthalmol.
104, 1013-1020 (1986).
3. Weleber. et al., “Aaland Island Eye Disease (Forsius-Eriksson syndrome) associated with contiguous deletion syndrome at Xp21
”, Arch. Ophthalmol
107:1170-1179.
4. Boycott, et al., “Evidence for genetic heterogeneity in X-linked congenital stationary night blindness.”
Am. J. Hum. Genet.
62:865-875 (1998).
5. Catterall, “Structure and function of voltage-gated ion channels”.
Annu. Rev. Biochem.
64, 493-531 (1995).
6. Fishman and Sokol, “
Electrophysiologic Testing in Disorders of the Retina, Optic Nerve, and Visual Pathway
”, (Am. Acad. Ophthal., San Francisco, 1990).
7. Wilkinson and Barnes, “The dihydropyridine-sensitive calcium channel subtype in cone photoreceptors”,
J. Gen. Physiol.
107, 621-630 (1996).
8. Boycott, et al., “A 2-megabase physical contig incorporating 43 DNA markers on the human X chromosome at p11.23-p11.22 from ZNF21 to DXS255
”, Genomics
33, 488-497 (1996).
9. Schindelhauer, et al., “Long-range mapping of a 3.5-MB region in Xp11.23-22 with a sequence-ready map from a 1.1-Mb gene-rich interval”,
Genome Res
6. 1056-1069 (1996).
10. Boycott, et al., “Construction of a 1.5 Mb bacterial artificial chromosome (BAC) contig in Xp11.23, a region of high gene content”
Genomics,
48:369-372 (1998).
11. Fisher, et al., “Sequence-based exon prediction around the synaptophysin locus reveals a gene-rich area containing novel genes in human proximal Xp”.
Genomics
45, 340-347 (1997).
12. Williams, et al., “Structure and functional expression of a &agr;1, &agr;2, and &bgr; subunits of a novel human neuronal calcium channel subtype”,
Neuron
8, 71-84 (1992).
13. Schuster, et al., “The IVS6 segment of the L-type calcium channel is critical for the action of dihydropyridines and phenylalkylamine”,
EMBO J.
15.2365-2370 (1996).
14. Boycott, et al., “Integration of 101 DNA markers across human Xp11 using a panel of somatic cell hybrids”,
Cell Cytogenet. Genet.
76. 223-228 (1997).
15. Nathans and Hogness, “Isolation, sequence analysis, and intron-exon arrangement of the gene encoding bovine rhodopsin”,
Cell
34, 807-814 (1983).
16. Bech-Hansen, et al., “Loss-of-function mutations in a calcium-channel &agr;
1
-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness”,
Nature Genet.
19: 264-267 (1998).
BACKGROUND
X-linked congenital stationary night blindness (CSNB) is a non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus [1]. Two distinct clinical entities of CSNB have been proposed, complete and incomplete CSNB [2]. In patients with complete CSNB, rod function is not detectable, whereas patients with incomplete CSNB have reduced, but not extinguished rod function. Furthermore, patients with complete CSNB may show moderate to severe myopia, whereas those with incomplete CSNB may show severe myopia to hyperopia [1]. A related disorder, Aaland Island eye disease (AIED), is suggested to be clinically indistinguishable from incomplete CSNB [3].
The biochemical defects underlying complete and incomplete CSNB are not known, but may be revealed by identifying the genes involved in these disorders. The CSNB gene(s) has been localized to the short arm of the human X-chromosome to region p11 by linkage analysis. However, it was uncertain whether the phenotypic variation results from genetic heterogeneity or a single locus exhibiting a wide variation in clinical phenotype [4]. Studies of three families with AIED have localized the AIED gene between DXS7 DXS255, overlapping with the chromosomal region harbouring the gene for incomplete CSNB.
Calcium channels are membrane-spanning hetero-oligomeric protein complexes, consisting of (alpha)
1
, (alpha)
2
, (beta)
1
, (beta)
2
, delta and gamma subunits [5], that allow controlled entry of Ca
2+
ions into the cytoplasm from the extracellular space or from intracellular stores. All cells throughout the animal kingdom and some plant, bacteria and fungal cells possess one or more types of calcium channel, which play a central role in the regulation of intracellular Ca
2+
concentration. Changes in intracellular Ca
2+
concentration are implicated in a number of vital processes, such as neurotransmitter release, muscle contraction, pacemaker activity and the secretion of hormones and other substances.
Voltage-gated calcium channels (types L, N, and P) are located on the plasma membrane of all excitable animal cells, such as neurons and muscle cells. L-type voltage-gated channels are distinguished pharmacologically from the other types by, among other features, their ability to bind dihydropyridine.
The (alpha)
1
-subunits of L-type channels function as the pore and voltage sensors in calcium ion-selective pores [5]. Several diseases are known to be the result of mutations in calcium channel (alpha)
1
-subunit genes, including human familial hemiplegic migraine and episodic ataxia type-2, hypokalemic periodic paralysis, muscular dysgenesis (mdg) and absence epilepsy in tottering mice. Mutations in an L-type calcium channel (alpha)
1
-subunit gene cause myotonia in
C. elegans,
and a non L-type calcium channel (alpha)
1
-subunit gene in Drosophilia (DmcalA) is a suggested candidate gene for the night-blind-A (nbA) and cacophony (cac) mutations.
Patients with CSNB, both complete and incomplete, show a reduced b-wave response on electroretinographic testing and decreased dark adaptation. Light-induced hyperpolarization of photoreceptor cells diminishes the release of neurotransmitters at their synaptic terminals, which in turn leads to the depolarization of outer nuclear bipolar and horizontal cells. This depolarization of bipolar cells causes the subsequent depolarization of Mueller cells, which appears largely to be the origin of the corneal positive b-wave [6]. The influx of calcium through dihydropyridine-sensitive calcium channels into photoreceptor cells has been shown to mediate the release of neurotransmitter [7]. Therefore, it is reasonable to presume that one or more L-type voltage-gated channels is involved in neurotransmission in the eye.
High-density physical maps of the Xp11.23 cytogenetic region have been constructed in YACs [8], cosmids [9], and BACs [10]. Large scale DNA sequencing in the Xp11.23 region has revealed several new genes. Computer analysis (GRAIL™ and GENE-ID™) of an extended genomic DNA sequence within the Xp11.23 region, has identified potential exons with homology to calcium channel (alpha)
1
-subunit genes [28]. There was an indication that this gene was expressed in skeletal muscle, but this assertion may not be supported by the reported data [28]. The HUGO/GDB Nomenclature Committee has assigned this putative gene the name CACNA1F. The same putative gene was identified by the GENSCAN™, in a computer search of about 1,000 Kb of genomic DNA in this region (Xp11.23) by the Genome Sequencing Centre, Jena.
The identification of the gene which is causative of incomplete CSNB may allow for development of diagnostic tests for this disorder and ri
Bech-Hansen Torben
Naylor Margaret Jane
Bennett Jones LLP
Brannock Michael
Kemmerer Elizabeth
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