Disease relevance of CACNA1F

• Novel mutations in CACNA1F and NYX in Dutch families with X-linked congenital stationary night blindness [1].
• JM8 (cisplatin analogue) alone for previously untreated advanced ovarian carcinoma [2].
• Carboplatin (Paraplatin; JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer [3].
• Preliminary results with JM8 suggest that it is an active single agent in the treatment of seminoma [4].
• cis-Diammine-1,1-cyclobutane dicarboxylate platinum II (CBDCA, JM8), an analogue of cisplatin showing reduced toxicity in preclinical studies, was evaluated in 60 patients [5].

High impact information on CACNA1F

• These two genetic subtypes can be distinguished on the basis of electroretinogram (ERG) responses and psychophysical testing as a complete (CSNB1) and an incomplete (CSNB2) form [6].
• Mutation analysis of this new alpha1-subunit gene, CACNA1F, in 20 families with incomplete CSNB revealed six different mutations that are all predicted to cause premature protein truncation [7].
• CACNA1F encodes the alpha (1)-subunit of an L-type Ca(2+) channel (Cav1.4 alpha ), which is specific to photoreceptors and is present at high density in the synaptic terminals [8].
• The CACNA1F gene encodes the poreforming subunit of the Ca(v)1.4 channel and various mutations in CACNA1F cause X-linked incomplete congenital stationary night blindness (CSNB2) [9].
• Molecular genetic analyses identified a previously undescribed nucleotide substitution in CACNA1F that is predicted to encode an isoleucine to threonine substitution at CACNA1F residue 745 [9].

Chemical compound and disease context of CACNA1F

• Carboplatin (JM8) as a single agent and in combination in the treatment of small cell lung cancer [10].
• Advanced seminoma: treatment with cis-platinum-based combination chemotherapy or carboplatin (JM8) [4].
• A pilot study of carboplatin (JM8, CBDCA) and chlorambucil in combination for advanced ovarian cancer [11].
• Forty patients with either metastatic, post-radiotherapy recurrent, or poor prognosis locally advanced transitional cell carcinoma of the bladder were treated in a new combination chemotherapy programme with methotrexate, vinblastine, mitozantrone and JM8 (carboplatin); 33 patients were assessable for response [12].

Biological context of CACNA1F

• 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 Aland Island eye disease (AIED)-like [13].
• Molecular genetic testing by denaturing high performance liquid chromatography (DHPLC), single stranded conformation polymorphism (SSCP) analysis, and direct sequencing of the CACNA1F and NYX genes were performed in the patients possessing a negative Schubert Bornschein ERG [1].
• The I745T CACNA1F allele produced a remarkable approximately -30-mV shift in the voltage dependence of Ca(v)1.4 channel activation and significantly slower inactivation kinetics in an expression system [9].
• INTERPRETATION: Although the patients shared a common CACNA1F mutation, there was considerable variability in the clinical expression of the incomplete CSNB phenotype [14].
• The CACNA1F gene encodes an L-type calcium channel with unique biophysical properties and tissue distribution [15].

Anatomical context of CACNA1F

• CACNA1F encodes the Ca(v)1.4 alpha1 subunit of a voltage-gated calcium channel, which may mediate neurotransmitter release from photoreceptors [16].
• Genomic DNA was extracted from leukocytes of the peripheral blood, and all 48 exons of the CACNA1F were amplified by polymerase chain reaction and directly sequenced [17].
• All 3 CSNB patients with evidence for optic nerve fibre mis-routing had X-linked pedigrees: 2 had an identified mutation in the NYX gene but no mutation in either the NYX or CACNA1F genes was identified in the third [18].
• The comparative antitumour activity of cisplatin, JM8 and JM9 was tested using a panel of different heterotransplanted human testicular tumour cell lines [19].
• From these data it is concluded that the antitumor activity of cisplatin may be significantly superior to JM8 and JM9, and results of preclinical investigations should be awaited before replacement of cisplatin by JM8 or JM9 in the treatment of nonseminomatous germ cell tumors can be considered [20].

Associations of CACNA1F with chemical compounds

• Quantitative ultrastructural effects of cisplatin (Platinol), carboplatin (JM8), and iproplatin (JM9) on neurons of freshwater snail Lymnaea stagnalis [21].
• cis-Diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA, JM8) is a nonnephrotoxic analogue of cisplatin currently undergoing clinical evaluation [22].
• We compared cisplatin (cis-DDP) and two of its analogues, carboplatin (JM8, CBDCA) and iproplatin (JM9, CHIP) for their ability to retard the growth of multicellular tumour spheroids [23].
• Carboplatin (JM8) was given at the dose of 230 mg/m2 and mitoxantrone at the dose of 9 mg/m2 every 28 days [24].
• The blood and urinary clearances of cis-diammine 1,1-cyclobutane dicarboxylate platinum(II) (CBDCA, JM8) were determined in four patients with malignancy [25].

Other interactions of CACNA1F

• Rod responses were less severely affected in the CACNA1F and RS1 groups and ERGs did not differ significantly between these two groups [26].
• In the present study, we recruited 142 male schizophrenic patients and their biological mothers from all parts of the United Kingdom to detect a genetic association for the SYP/CACNA1F locus in the Xp11 region and the FACL4 locus in the Xq22.3-Xq23 region [27].
• X linked cone-rod dystrophy, CORDX3, is caused by a mutation in the CACNA1F gene [28].

Analytical, diagnostic and therapeutic context of CACNA1F

• Sequence alterations in CACNA1F lead to the incomplete type of CSNB (CSNB2), which can be distinguished by standard electroretinography (ERG) [8].
• Early clinical studies in which JM8 has been shown to be effective in the treatment of ovarian carcinoma support the view that xenograft tumours may have a role in phase-II screening of new cytotoxic agents [29].
• Urinary protein and enzyme excretion was measured in 33 patients with solid tumours receiving chemotherapy with the cis-platinum analogs carboplatin (JM8, CBDCA) and iproplatin (JM9, CHIP) [30].

References