Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex

C4RCD Research Group

doi:10.1038/s41467-020-17105-8

Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex

C4RCD Research Group

Department of Cellular and Molecular Physiology

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

The sodium-leak channel NALCN forms a subthreshold sodium conductance that controls the resting membrane potentials of neurons. The auxiliary subunits of the channel and their functions in mammals are largely unknown. In this study, we demonstrate that two large proteins UNC80 and UNC79 are subunits of the NALCN complex. UNC80 knockout mice are neonatal lethal. The C-terminus of UNC80 contains a domain that interacts with UNC79 and overcomes a soma-retention signal to achieve dendritic localization. UNC80 lacking this domain, as found in human patients, still supports whole-cell NALCN currents but lacks dendritic localization. Our results establish the subunit composition of the NALCN complex, uncover the inter-subunit interaction domains, reveal the functional significance of regulation of dendritic membrane potential by the sodium-leak channel complex, and provide evidence supporting that genetic variations found in individuals with intellectual disability are the causes for the phenotype observed in patients.

Original language	English (US)
Article number	3351
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17105-8
State	Published - Dec 1 2020

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-020-17105-8

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@article{0b24106c8edb44c090c88cb598f87415,

title = "Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex",

abstract = "The sodium-leak channel NALCN forms a subthreshold sodium conductance that controls the resting membrane potentials of neurons. The auxiliary subunits of the channel and their functions in mammals are largely unknown. In this study, we demonstrate that two large proteins UNC80 and UNC79 are subunits of the NALCN complex. UNC80 knockout mice are neonatal lethal. The C-terminus of UNC80 contains a domain that interacts with UNC79 and overcomes a soma-retention signal to achieve dendritic localization. UNC80 lacking this domain, as found in human patients, still supports whole-cell NALCN currents but lacks dendritic localization. Our results establish the subunit composition of the NALCN complex, uncover the inter-subunit interaction domains, reveal the functional significance of regulation of dendritic membrane potential by the sodium-leak channel complex, and provide evidence supporting that genetic variations found in individuals with intellectual disability are the causes for the phenotype observed in patients.",

author = "{C4RCD Research Group} and Jinhong Wie and Apoorva Bharthur and Morgan Wolfgang and Vinodh Narayanan and Keri Ramsey and Newell Belnap and Ana Claasen and Amanda Courtright and {de Both}, Matt and Matthew Huentelman and Sampathkumar Rangasamy and Ryan Richholt and Isabelle Schrauwen and Siniard, {Ashley L.} and Szabolics Szelinger and Kimberly Aranda and Qi Zhang and Yandong Zhou and Dejian Ren",

note = "Funding Information: We thank members of the Ren lab for pilot experiments and discussions. We are grateful to the Transgenic and Chimeric Mouse Core of the University of Pennsylvania for generation of all the transgenic lines (supported by NIH center grants P30DK050306, P30DK019525, and P30CA016520). The work was supported, in part, by NIH grants 1R01NS055293 and 1R01NS074257. The authors would like to thank the family for their participation in the study. We also acknowledge the contributions of the C4RCD Research Group for patient enrollment, sample processing, exome sequencing, data processing, preparation of variant annotation files, data analysis, validation of data, and return of research data to families. The following members of the group (listed in alphabetical order) have contributed significantly to this work: N.B. (nbelnap@tgen.org), A.C. (ana.claasen@gmail.com), A.C. (acourtright@tgen.org), David Craig (davidwcr@usc. edu), M.d.B. (mdeboth@tgen.org), M.H. (mhuentelman@tgen.org), S.R. (srangasa-my@tgen.org), R.R. (rrichholt@tgen.org), I.S. (isabelle.schrauwen@gmail.com), A.L.S. (Ashley.Siniard@gmail.com), S.S. (sszelinger@tgen.org). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-17105-8",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex

AU - C4RCD Research Group

AU - Wie, Jinhong

AU - Bharthur, Apoorva

AU - Wolfgang, Morgan

AU - Narayanan, Vinodh

AU - Ramsey, Keri

AU - Belnap, Newell

AU - Claasen, Ana

AU - Courtright, Amanda

AU - de Both, Matt

AU - Huentelman, Matthew

AU - Rangasamy, Sampathkumar

AU - Richholt, Ryan

AU - Schrauwen, Isabelle

AU - Siniard, Ashley L.

AU - Szelinger, Szabolics

AU - Aranda, Kimberly

AU - Zhang, Qi

AU - Zhou, Yandong

AU - Ren, Dejian

N1 - Funding Information: We thank members of the Ren lab for pilot experiments and discussions. We are grateful to the Transgenic and Chimeric Mouse Core of the University of Pennsylvania for generation of all the transgenic lines (supported by NIH center grants P30DK050306, P30DK019525, and P30CA016520). The work was supported, in part, by NIH grants 1R01NS055293 and 1R01NS074257. The authors would like to thank the family for their participation in the study. We also acknowledge the contributions of the C4RCD Research Group for patient enrollment, sample processing, exome sequencing, data processing, preparation of variant annotation files, data analysis, validation of data, and return of research data to families. The following members of the group (listed in alphabetical order) have contributed significantly to this work: N.B. (nbelnap@tgen.org), A.C. (ana.claasen@gmail.com), A.C. (acourtright@tgen.org), David Craig (davidwcr@usc. edu), M.d.B. (mdeboth@tgen.org), M.H. (mhuentelman@tgen.org), S.R. (srangasa-my@tgen.org), R.R. (rrichholt@tgen.org), I.S. (isabelle.schrauwen@gmail.com), A.L.S. (Ashley.Siniard@gmail.com), S.S. (sszelinger@tgen.org). Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The sodium-leak channel NALCN forms a subthreshold sodium conductance that controls the resting membrane potentials of neurons. The auxiliary subunits of the channel and their functions in mammals are largely unknown. In this study, we demonstrate that two large proteins UNC80 and UNC79 are subunits of the NALCN complex. UNC80 knockout mice are neonatal lethal. The C-terminus of UNC80 contains a domain that interacts with UNC79 and overcomes a soma-retention signal to achieve dendritic localization. UNC80 lacking this domain, as found in human patients, still supports whole-cell NALCN currents but lacks dendritic localization. Our results establish the subunit composition of the NALCN complex, uncover the inter-subunit interaction domains, reveal the functional significance of regulation of dendritic membrane potential by the sodium-leak channel complex, and provide evidence supporting that genetic variations found in individuals with intellectual disability are the causes for the phenotype observed in patients.

AB - The sodium-leak channel NALCN forms a subthreshold sodium conductance that controls the resting membrane potentials of neurons. The auxiliary subunits of the channel and their functions in mammals are largely unknown. In this study, we demonstrate that two large proteins UNC80 and UNC79 are subunits of the NALCN complex. UNC80 knockout mice are neonatal lethal. The C-terminus of UNC80 contains a domain that interacts with UNC79 and overcomes a soma-retention signal to achieve dendritic localization. UNC80 lacking this domain, as found in human patients, still supports whole-cell NALCN currents but lacks dendritic localization. Our results establish the subunit composition of the NALCN complex, uncover the inter-subunit interaction domains, reveal the functional significance of regulation of dendritic membrane potential by the sodium-leak channel complex, and provide evidence supporting that genetic variations found in individuals with intellectual disability are the causes for the phenotype observed in patients.

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U2 - 10.1038/s41467-020-17105-8

DO - 10.1038/s41467-020-17105-8

M3 - Article

C2 - 32620897

AN - SCOPUS:85087427748

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 3351

ER -

Intellectual disability-associated UNC80 mutations reveal inter-subunit interaction and dendritic function of the NALCN channel complex

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