A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking

Swati Khare, Jerelyn A. Nick, Yalan Zhang, Kira Galeano, Brittany Butler, Habibeh Khoshbouei, Sruti Rayaprolu, Tyisha Hathorn, Laura P.W. Ranum, Lisa Smithson, Todd E. Golde, Martin Paucar, Richard Morse, Michael Raff, Julie Simon, Magnus Nordenskjold, Karin Wirdefeldt, Diego E. Rincon-Limas, Jada Lewis, Leonard K. KaczmarekPedro Fernandez-Funez, Harry S. Nick, Michael F. Waters

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.

Original languageEnglish (US)
Article numbere0173565
JournalPloS one
Volume12
Issue number5
DOIs
StatePublished - May 2017

Fingerprint

Epidermal Growth Factor Receptor
Drosophila
mutation
Mutation
eyes
Cells
Pathology
Phenotype
phenotype
inheritance (genetics)
Alleles
Glycosylation
alleles
ataxia (disorder)
Spinocerebellar Ataxias
Voltage-Gated Potassium Channels
ommatidia
Dysarthria
Cerebellar Ataxia
mutants

Cite this

A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking. / Khare, Swati; Nick, Jerelyn A.; Zhang, Yalan; Galeano, Kira; Butler, Brittany; Khoshbouei, Habibeh; Rayaprolu, Sruti; Hathorn, Tyisha; Ranum, Laura P.W.; Smithson, Lisa; Golde, Todd E.; Paucar, Martin; Morse, Richard; Raff, Michael; Simon, Julie; Nordenskjold, Magnus; Wirdefeldt, Karin; Rincon-Limas, Diego E.; Lewis, Jada; Kaczmarek, Leonard K.; Fernandez-Funez, Pedro; Nick, Harry S.; Waters, Michael F.

In: PloS one, Vol. 12, No. 5, e0173565, 05.2017.

Research output: Contribution to journalArticle

Khare, S, Nick, JA, Zhang, Y, Galeano, K, Butler, B, Khoshbouei, H, Rayaprolu, S, Hathorn, T, Ranum, LPW, Smithson, L, Golde, TE, Paucar, M, Morse, R, Raff, M, Simon, J, Nordenskjold, M, Wirdefeldt, K, Rincon-Limas, DE, Lewis, J, Kaczmarek, LK, Fernandez-Funez, P, Nick, HS & Waters, MF 2017, 'A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking', PloS one, vol. 12, no. 5, e0173565. https://doi.org/10.1371/journal.pone.0173565
Khare, Swati ; Nick, Jerelyn A. ; Zhang, Yalan ; Galeano, Kira ; Butler, Brittany ; Khoshbouei, Habibeh ; Rayaprolu, Sruti ; Hathorn, Tyisha ; Ranum, Laura P.W. ; Smithson, Lisa ; Golde, Todd E. ; Paucar, Martin ; Morse, Richard ; Raff, Michael ; Simon, Julie ; Nordenskjold, Magnus ; Wirdefeldt, Karin ; Rincon-Limas, Diego E. ; Lewis, Jada ; Kaczmarek, Leonard K. ; Fernandez-Funez, Pedro ; Nick, Harry S. ; Waters, Michael F. / A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking. In: PloS one. 2017 ; Vol. 12, No. 5.
@article{7f310f6969b44e0480fe6687d6ac95cc,
title = "A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking",
abstract = "The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.",
author = "Swati Khare and Nick, {Jerelyn A.} and Yalan Zhang and Kira Galeano and Brittany Butler and Habibeh Khoshbouei and Sruti Rayaprolu and Tyisha Hathorn and Ranum, {Laura P.W.} and Lisa Smithson and Golde, {Todd E.} and Martin Paucar and Richard Morse and Michael Raff and Julie Simon and Magnus Nordenskjold and Karin Wirdefeldt and Rincon-Limas, {Diego E.} and Jada Lewis and Kaczmarek, {Leonard K.} and Pedro Fernandez-Funez and Nick, {Harry S.} and Waters, {Michael F.}",
year = "2017",
month = "5",
doi = "10.1371/journal.pone.0173565",
language = "English (US)",
volume = "12",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking

AU - Khare, Swati

AU - Nick, Jerelyn A.

AU - Zhang, Yalan

AU - Galeano, Kira

AU - Butler, Brittany

AU - Khoshbouei, Habibeh

AU - Rayaprolu, Sruti

AU - Hathorn, Tyisha

AU - Ranum, Laura P.W.

AU - Smithson, Lisa

AU - Golde, Todd E.

AU - Paucar, Martin

AU - Morse, Richard

AU - Raff, Michael

AU - Simon, Julie

AU - Nordenskjold, Magnus

AU - Wirdefeldt, Karin

AU - Rincon-Limas, Diego E.

AU - Lewis, Jada

AU - Kaczmarek, Leonard K.

AU - Fernandez-Funez, Pedro

AU - Nick, Harry S.

AU - Waters, Michael F.

PY - 2017/5

Y1 - 2017/5

N2 - The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.

AB - The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.

UR - http://www.scopus.com/inward/record.url?scp=85018756770&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018756770&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0173565

DO - 10.1371/journal.pone.0173565

M3 - Article

C2 - 28467418

AN - SCOPUS:85018756770

VL - 12

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e0173565

ER -