Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Lehman, Anna; Thouta, Samrat; Mancini, Grazia M.S.; Naidu, Sakkubai; Slegtenhorst, Marjon van; McWalter, Kirsty; Person, Richard; Mwenifumbo, Jill; Salvarinova, Ramona; Adam, Shelin; Souich, Christèle du; Elliott, Alison M.; Nelson, Tanya N.; Karnebeek, Clara van; Friedman, Jan M.; Boelman, Cyrus; Bolbocean, Corneliu; Buerki, Sarah E.; Candido, Tara; Eydoux, Patrice; Evans, Daniel M.; Gibson, William T.; Horváth, Gabriella; Huh, Linda; Sinclair, Graham; Tarling, Tamsin; Toyota, Eric B.; Townsend, Katelin N.; Allen, Margot I. Van; Vercauteren, Suzanne; Guella, Ilaria; McKenzie, Michael; Datta, Anita; Connolly, Mary; Kalkhoran, Somayeh Mojard; Poburko, Damon; Farrer, Matthew J.; Demos, Michelle; Desai, Sonal; Claydon, Tom W.

doi:10.1016/j.ajhg.2017.05.016

Cited by 96 publications

(80 citation statements)

References 30 publications

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“…Here, we found cilantro extract and specifically (E)-2-dodecenal, previously identified as the predominant component of cilantro leaf oil (35), to be a highly efficacious KCNQ5 activator, suggesting a possible molecular basis contributing to the historical use of cilantro and culantro as folk hypotensives, an application that was recently verified using cilantro crude extract in animal studies (47). KCNQ5 gene variants (48) and aberrant splicing (49) that impair its function cause epilepsy (and severe intellectual disability), suggesting its activation could also contribute to the anticonvulsant action of cilantro [and (E)-2-dodecenal].…”

Section: Discussionmentioning

confidence: 53%

Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

Manville

Abbott

2019

FASEB j.

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Herbs have a long history of use as folk medicine anticonvulsants, yet the underlying mechanisms often remain unknown. Neuronal voltage‐gated potassium channel subfamily Q (KCNQ) dysfunction can cause severe epileptic encephalopathies that are resistant to modern anticonvulsants. Here we report that cilantro (Coriandrum sativum), a widely used culinary herb that also exhibits antiepileptic and other therapeutic activities, is a highly potent KCNQ channel activator. Screening of cilantro leaf metabolites revealed that one, the long‐chain fatty aldehyde (E)‐2‐dodecenal, activates multiple KCNQs, including the predominant neuronal isoform, KCNQ2/ KCNQ3 [half maximal effective concentration (EC50), 60 ± 20 nM], and the predominant cardiac isoform, KCNQ1 in complexes with the type I transmembrane ancillary subunit (KCNE1) (EC50, 260 ± 100 nM). (E)‐2‐dodecenal also recapitulated the anticonvulsant action of cilantro, delaying pentylene tetrazole‐induced seizures. In silico docking and mutagenesis studies identified the (E)‐2‐dodecenal binding site, juxtaposed between residues on the KCNQ S5 transmembrane segment and S4‐5 linker. The results provide a molecular basis for the therapeutic actions of cilantro and indicate that this ubiquitous culinary herb is surprisingly influential upon clinically important KCNQ channels.—Manville, R. W., Abbott, G. W. Cilantro leaf harbors a potent potassium channel‐activating anticonvulsant. FASEB J. 33, 11349–11363 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 53%

Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

Manville

Abbott

2019

FASEB j.

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“…Of interest, different CACNA1A GOF and LOF mutations have also been recently associated with developmental ataxia, global developmental delay, and progressive cerebellar atrophy in children, suggesting that CACNA1A mutations with opposite functional impact can have similar severe developmental presentations. Furthermore, both GOF or LOF mutations in other neuronal channels have been associated with DEE of variable severity ( SCN1A, KCNQ2, KCNQ5, KCNA2 and KCNB1 ).…”

Section: Discussionmentioning

confidence: 99%

Both gain‐of‐function and loss‐of‐function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox‐Gastaut syndrome

et al. 2019

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Objective Developmental epileptic encephalopathies (DEEs) are genetically heterogeneous severe childhood‐onset epilepsies with developmental delay or cognitive deficits. In this study, we explored the pathogenic mechanisms of DEE‐associated de novo mutations in the CACNA1A gene. Methods We studied the functional impact of four de novo DEE‐associated CACNA1A mutations, including the previously described p.A713T variant and three novel variants (p.V1396M, p.G230V, and p.I1357S). Mutant cDNAs were expressed in HEK293 cells, and whole‐cell voltage‐clamp recordings were conducted to test the impacts on CaV2.1 channel function. Channel localization and structure were assessed with immunofluorescence microscopy and three‐dimensional (3D) modeling. Results We find that the G230V and I1357S mutations result in loss‐of‐function effects with reduced whole‐cell current densities and decreased channel expression at the cell membrane. By contrast, the A713T and V1396M variants resulted in gain‐of‐function effects with increased whole‐cell currents and facilitated current activation (hyperpolarized shift). The A713T variant also resulted in slower current decay. 3D modeling predicts conformational changes favoring channel opening for A713T and V1396M. Significance Our findings suggest that both gain‐of‐function and loss‐of‐function CACNA1A mutations are associated with similarly severe DEEs and that functional validation is required to clarify the underlying molecular mechanisms and to guide therapies.

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“…We also observed enrichment of multiple terms associated with neuronal functions including ionotropic glutamate receptor activity, neurotransmitter secretion, and voltage-gated potassium channel activity. The latter group includes transcripts from the genes KCNQ5, KCNA4, KCNV1, KCND3, KCNT2, and KCNQ2, which are voltage-gated potassium channels that are expressed in the brain and are linked to neurological disorders including intellectual disability, microcephaly, seizures, movement disorders, and spinocerebellar ataxia (42,43). These results provide new evidence that NOCT is capable of downregulating neuronal transcripts and suggests a new biological role for cytoplasmic NOCT.…”

Section: Impact Of Cytoplasmic Noct On the Transcriptomementioning

confidence: 74%

Differential processing and localization of human Nocturnin controls metabolism of mRNA and nicotinamide dinucleotide metabolites

Abshire

Hughes

Diao

et al. 2020

Preprint

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Nocturnin (NOCT) is a eukaryotic enzyme that belongs to a superfamily of exoribonucleases, endonucleases, and phosphatases. In this study, we analyze the expression, processing, localization, and cellular functions of human NOCT. We demonstrate that the NOCT protein is differentially expressed and processed in a cell and tissue type specific manner as a means to control its localization to the cytoplasm or mitochondria. Our studies also show that the N-terminus of NOCT is necessary and sufficient to confer mitochondrial localization. We then measured the impact of cytoplasmic NOCT on the transcriptome and report that it regulates the levels of hundreds of mRNAs that are enriched for components of signaling pathways, neurological functions, and regulators of osteoblast differentiation. Recent biochemical data indicate that NOCT dephosphorylates nicotinamide adenine dinucleotide (NAD) metabolites, and thus we measured the effect of NOCT on these cofactors in cells. We find that NOCT increases NAD(H) and decreases NADP(H) levels in a manner dependent on its intracellular localization. Collectively, our data indicate that NOCT can regulate levels of both mRNAs and NADP(H) cofactors in manner specified by its intracellular localization.

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Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Cited by 96 publications

References 30 publications

Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

Both gain‐of‐function and loss‐of‐function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox‐Gastaut syndrome

Differential processing and localization of human Nocturnin controls metabolism of mRNA and nicotinamide dinucleotide metabolites

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