Zhang, Yongqiang, Tachtsidis, Georgios, Schob, Claudia, Koko, Mahmoud ORCID: 0000-0001-9512-0184, Hedrich, Ulrike B. S., Lerche, Holger, Lemke, Johannes R., van Haeringen, Arie, Ruivenkamp, Claudia, Prescott, Trine, Tveten, Kristian, Gerstner, Thorsten, Pruniski, Brianna, DiTroia, Stephanie, VanNoy, Grace E., Rehm, Heidi L., McLaughlin, Heather, Bolz, Hanno J., Zechner, Ulrich, Bryant, Emily, McDonough, Tiffani, Kindler, Stefan and Baehring, Robert (2021). KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating. Hum. Mol. Genet., 30 (23). S. 2300 - 2315. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Here, we report on six unrelated individuals, all presenting with early-onset global developmental delay, associated with impaired motor, speech and cognitive development, partly with developmental epileptic encephalopathy and physical dysmorphisms. All individuals carry heterozygous missense variants of KCND2, which encodes the voltage-gated potassium (Kv) channel alpha-subunit Kv4.2. The amino acid substitutions associated with the variants, p.(Glu323Lys) (E323K), p.(Pro403Ala) (P403A), p.(Val404Leu) (V404L) and p.(Val404Met) (V404M), affect sites known to be critical for channel gating. To unravel their likely pathogenicity, recombinant mutant channels were studied in the absence and presence of auxiliary beta-subunits under two-electrode voltage clamp in Xenopus oocytes. All channel mutants exhibited slowed and incomplete macroscopic inactivation, and the P403A variant in addition slowed activation. Co-expression of KChIP2 or DPP6 augmented the functional expression of both wild-type and mutant channels; however, the auxiliary beta-subunit-mediated gating modifications differed from wild type and among mutants. To simulate the putative setting in the affected individuals, heteromeric Kv4.2 channels (wild type + mutant) were studied as ternary complexes (containing both KChIP2 and DPP6). In the heteromeric ternary configuration, the E323K variant exhibited only marginal functional alterations compared to homomeric wild-type ternary, compatible with mild loss-of-function. By contrast, the P403A, V404L and V404M variants displayed strong gating impairment in the heteromeric ternary configuration, compatible with loss-of-function or gain-of-function. Our results support the etiological involvement of Kv4.2 channel gating impairment in early-onset monogenic global developmental delay. In addition, they suggest that gain-of-function mechanisms associated with a substitution of V404 increase epileptic seizure susceptibility.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Zhang, YongqiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tachtsidis, GeorgiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schob, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koko, MahmoudUNSPECIFIEDorcid.org/0000-0001-9512-0184UNSPECIFIED
Hedrich, Ulrike B. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemke, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Haeringen, ArieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruivenkamp, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prescott, TrineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tveten, KristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerstner, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pruniski, BriannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DiTroia, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
VanNoy, Grace E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rehm, Heidi L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McLaughlin, HeatherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolz, Hanno J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zechner, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bryant, EmilyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McDonough, TiffaniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kindler, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baehring, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-604041
DOI: 10.1093/hmg/ddab192
Journal or Publication Title: Hum. Mol. Genet.
Volume: 30
Number: 23
Page Range: S. 2300 - 2315
Date: 2021
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CLOSED-STATE INACTIVATION; GATED POTASSIUM CHANNEL; K+ CHANNEL; ALTERED EXPRESSION; PROTEIN; LOCALIZATION; MODULATION; SUBUNITS; BINDING; PHOSPHORYLATIONMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60404

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