KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating

Yongqiang Zhang; Georgios Tachtsidis; Claudia Schob; Mahmoud Koko; Ulrike B S Hedrich; Holger Lerche; Johannes R Lemke; Arie van Haeringen; Claudia Ruivenkamp; Trine Prescott; Kristian Tveten; Thorsten Gerstner; Brianna Pruniski; Stephanie DiTroia; Grace E VanNoy; Heidi L Rehm; Heather McLaughlin; Hanno J Bolz; Ulrich Zechner; Emily Bryant; Tiffani McDonough; Stefan Kindler; Robert Bähring

doi:10.1093/hmg/ddab192

KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating

Standard

KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating. / Zhang, Yongqiang; Tachtsidis, Georgios; Schob, Claudia; Koko, Mahmoud; 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 ; Bähring, Robert.

In: HUM MOL GENET, Vol. 30, No. 23, 16.11.2021, p. 2300-2314.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Zhang, Y, Tachtsidis, G, Schob, C, Koko, M, Hedrich, UBS, Lerche, H, Lemke, JR, van Haeringen, A, Ruivenkamp, C, Prescott, T, Tveten, K, Gerstner, T, Pruniski, B, DiTroia, S, VanNoy, GE, Rehm, HL, McLaughlin, H, Bolz, HJ, Zechner, U, Bryant, E, McDonough, T, Kindler, S & Bähring, R 2021, 'KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating', HUM MOL GENET, vol. 30, no. 23, pp. 2300-2314. https://doi.org/10.1093/hmg/ddab192

APA

Zhang, Y., Tachtsidis, G., Schob, C., Koko, M., Hedrich, U. B. S., Lerche, H., Lemke, J. R., van Haeringen, A., Ruivenkamp, C., Prescott, T., Tveten, K., Gerstner, T., Pruniski, B., DiTroia, S., VanNoy, G. E., Rehm, H. L., McLaughlin, H., Bolz, H. J., Zechner, U., ... Bähring, R. (2021). KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating. HUM MOL GENET, 30(23), 2300-2314. https://doi.org/10.1093/hmg/ddab192

Vancouver

Zhang Y, Tachtsidis G, Schob C, Koko M, Hedrich UBS, Lerche H et al. KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating. HUM MOL GENET. 2021 Nov 16;30(23):2300-2314. https://doi.org/10.1093/hmg/ddab192

Bibtex

@article{3be2ece1661b4ac1a36a908c6d240ad2,

title = "KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating",

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 α-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 β-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 β-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.",

author = "Yongqiang Zhang and Georgios Tachtsidis and Claudia Schob and Mahmoud Koko and Hedrich, {Ulrike B S} and Holger Lerche and Lemke, {Johannes R} and {van Haeringen}, Arie and Claudia Ruivenkamp and Trine Prescott and Kristian Tveten and Thorsten Gerstner and Brianna Pruniski and Stephanie DiTroia and VanNoy, {Grace E} and Rehm, {Heidi L} and Heather McLaughlin and Bolz, {Hanno J} and Ulrich Zechner and Emily Bryant and Tiffani McDonough and Stefan Kindler and Robert B{\"a}hring",

year = "2021",

month = nov,

day = "16",

doi = "10.1093/hmg/ddab192",

language = "English",

volume = "30",

pages = "2300--2314",

journal = "HUM MOL GENET",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "23",

}

RIS

TY - JOUR

T1 - KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating

AU - Zhang, Yongqiang

AU - Tachtsidis, Georgios

AU - Schob, Claudia

AU - Koko, Mahmoud

AU - Hedrich, Ulrike B S

AU - Lerche, Holger

AU - Lemke, Johannes R

AU - van Haeringen, Arie

AU - Ruivenkamp, Claudia

AU - Prescott, Trine

AU - Tveten, Kristian

AU - Gerstner, Thorsten

AU - Pruniski, Brianna

AU - DiTroia, Stephanie

AU - VanNoy, Grace E

AU - Rehm, Heidi L

AU - McLaughlin, Heather

AU - Bolz, Hanno J

AU - Zechner, Ulrich

AU - Bryant, Emily

AU - McDonough, Tiffani

AU - Kindler, Stefan

AU - Bähring, Robert

PY - 2021/11/16

Y1 - 2021/11/16

N2 - 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 α-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 β-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 β-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.

AB - 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 α-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 β-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 β-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.

U2 - 10.1093/hmg/ddab192

DO - 10.1093/hmg/ddab192

M3 - SCORING: Journal article

C2 - 34245260

VL - 30

SP - 2300

EP - 2314

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 23

ER -