Burtscher, Verena, Schicker, Klaus ORCID: 0000-0002-3068-7830, Novikova, Elena, Poehn, Birgit, Stockner, Thomas ORCID: 0000-0002-7071-8283, Kugler, Christof ORCID: 0000-0003-0058-3106, Singh, Anamika, Zeitz, Christina ORCID: 0000-0002-3510-1712, Lancelot, Marie-Elise, Audo, Isabelle ORCID: 0000-0003-0698-5309, Leroy, Bart Peter, Freissmuth, Michael ORCID: 0000-0001-9398-1765, Herzig, Stefan, Matthes, Jan ORCID: 0000-0003-2754-1555 and Koschak, Alexandra (2014). Spectrum of Cav1.4 dysfunction in congenital stationary night blindness type 2. Biochim. Biophys. Acta-Biomembr., 1838 (8). S. 2053 - 2066. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 0006-3002

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Abstract

Defective retinal synaptic transmission in patients affected with congenital stationary night blindness type 2 (CSNB2) can result from different dysfunction phenotypes in Cav1.4L-type calcium channels. Here we investigated two prototypical Cav1.4 variants from either end of the functional spectrum. Using whole-cell and single-channel patch-clamp techniques, we provide analysis of the biophysical characteristics of the point mutation L860P and the C-terminal truncating mutation R1827X. L860P showed a typical loss-of-function phenotype attributed to a reduced number of functional channels expressed at the plasma membrane as implied by gating current and non-stationary noise analyses. This phenotype can be rationalized, because the inserted proline is predicted to break an amphipatic helix close to the transmembrane segment IIIS1 and thus to reduce channel stability and promote misfolding. In fact, L860P was subject to an increased turnover. In contrast, R1827X displayed an apparent gain-of-function phenotype, i.e., due to a hyperpolarizing shift of the IV-curve and increased single-channel activity. However, truncation also resulted in the loss of functional C-terminal modulation and thus unmasked calcium-dependent inactivation. Thus R1827X failed to support continuous calcium influx. Current inactivation curtails the dynamic range of photoreceptors (e.g., when adapting to variation in illumination). Taken together, the analysis of two representative mutations that occur in CSNB2 patients revealed fundamental differences in the underlying defect. These may explain subtle variations in the clinical manifestation and must be taken into account, if channel function is to be restored by pharmacochaperones or related approaches. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Burtscher, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schicker, KlausUNSPECIFIEDorcid.org/0000-0002-3068-7830UNSPECIFIED
Novikova, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poehn, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stockner, ThomasUNSPECIFIEDorcid.org/0000-0002-7071-8283UNSPECIFIED
Kugler, ChristofUNSPECIFIEDorcid.org/0000-0003-0058-3106UNSPECIFIED
Singh, AnamikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeitz, ChristinaUNSPECIFIEDorcid.org/0000-0002-3510-1712UNSPECIFIED
Lancelot, Marie-EliseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Audo, IsabelleUNSPECIFIEDorcid.org/0000-0003-0698-5309UNSPECIFIED
Leroy, Bart PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Freissmuth, MichaelUNSPECIFIEDorcid.org/0000-0001-9398-1765UNSPECIFIED
Herzig, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matthes, JanUNSPECIFIEDorcid.org/0000-0003-2754-1555UNSPECIFIED
Koschak, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-433149
DOI: 10.1016/j.bbamem.2014.04.023
Journal or Publication Title: Biochim. Biophys. Acta-Biomembr.
Volume: 1838
Number: 8
Page Range: S. 2053 - 2066
Date: 2014
Publisher: ELSEVIER SCIENCE BV
Place of Publication: AMSTERDAM
ISSN: 0006-3002
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RETINAL GENE-THERAPY; CALCIUM-CHANNEL; CA2+ CHANNELS; NEUROBLASTOMA-CELLS; SODIUM-CHANNELS; CACNA1F GENE; MUTATION; CA(V)1.3; DOMAIN; MOUSEMultiple languages
Biochemistry & Molecular Biology; BiophysicsMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43314

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