Intragenic duplication of KCNQ5 gene results in aberrant splicing leading to a premature termination codon in a patient with intellectual disability

Rosti, Giulia; Tassano, Elisa; Bossi, Simone; Divizia, Maria Teresa; Ronchetto, Patrizia; Servetti, Martina; Lerone, Margherita; Pisciotta, Livia; Mancardi, Maria Margherita; Veneselli, Edvige; Puliti, Aldamaria

doi:10.1016/j.ejmg.2018.10.007

Cited by 18 publications

(17 citation statements)

References 18 publications

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“…In four individuals, developmental delay or ID was present prior to epilepsy. The phenotype comprising absence seizures and ID is in accordance with a previous report of an individual with mild ID and absence seizures in adolescence, carrying an intragenic duplication in KCNQ5 leading to haploinsufficiency 17 . Lehman and colleagues reported four individuals suffering from ID and/or epilepsy caused by KCNQ5 variants.…”

Section: Discussionsupporting

confidence: 90%

“…individuals in family 3 exhibited a similarly severe phenotype albeit the p.Gln735Arg variant showed a less prominent electrophysiological dysfunction, and (iii) also the phenotype of previously reported individuals carrying variants which only caused a haploinsufficiency were reported with similar or more severe phenotypes 16,17 . This is in contrast to other K v 7 channels, in which functionally more severe variants with dominant-negative effects cause more severe epileptic phenotypes 36 .…”

Section: Discussionmentioning

confidence: 61%

“…These variants lead to a LOF by depolarizing shifts in activation, slowed activation kinetics or reduced cell surface expression in three individuals, or a gain-of-function (GOF) characterized by a hyperpolarizing shift in activation, accelerated activation kinetics and slowed deactivation kinetics in one of the DEE patients, who displayed the most severe phenotype of all 16 . Additionally, an individual presenting with absence seizures in adolescence, migraine and mild ID has recently been identified with an intragenic duplication of KCNQ5 most likely causing haploinsufficiency by skipping exons 2-11 and resulting in a premature stop codon 17 .…”

Section: Introductionmentioning

confidence: 99%

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Loss-of-function variants in the KCNQ5 gene are associated with genetic generalized epilepsies

Krueger

Schubert

Kegele

et al. 2021

Preprint

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Objective: De novo missense variants in KCNQ5, encoding the voltage–gated K+ channel KV7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease–related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods: 1292 families with GGE were studied by next-generation sequencing. Whole–cell patch–clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. Results: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss–of–function (LOF). When mutant channels were co–expressed with wild–type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant–negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P2–interaction, presumably in the non–conducting preopen–closed state. Interpretation: Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant–negative effects through functional, rather than trafficking deficits. LOF of KV7.5 channels will reduce the M–current, likely resulting in increased excitability of KV7.5–expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

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Loss-of-function variants in the KCNQ5 gene are associated with genetic generalized epilepsies

Krueger

Schubert

Kegele

et al. 2021

Preprint

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“…KCNQ5-selective openers based on aloperine, related molecules, or other compounds we have yet to uncover in the other hypotensive extracts with KCNQ5 activity may eventually be developed for clinical use for hypertension or, for example, KCNQ5 loss-of-function encephalopathies (32,33). Aloperine has proven hypotensive properties (59), and we show here that its vasorelaxant effects are KCNQ-dependent, being inhibited by the KCNQ channel inhibitor linopirdine.…”

Section: Discussionmentioning

confidence: 84%

KCNQ5 activation is a unifying molecular mechanism shared by genetically and culturally diverse botanical hypotensive folk medicines

Manville

Horst

Redford

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Botanical folk medicines have been used throughout human history to treat common disorders such as hypertension, often with unknown underlying mechanisms. Here, we discovered that hypotensive folk medicines from a genetically diverse range of plant species each selectively activated the vascular-expressed KCNQ5 potassium channel, a feature lacking in the modern synthetic pharmacopeia, whereas nonhypotensive plant extracts did not. Analyzing constituents of the hypotensive Sophora flavescens root, we found that the quinolizidine alkaloid aloperine is a KCNQ-dependent vasorelaxant that potently and isoform-selectively activates KCNQ5 by binding near the foot of the channel voltage sensor. Our findings reveal that KCNQ5-selective activation is a defining molecular mechanistic signature of genetically diverse traditional botanical hypotensives, transcending plant genus and human cultural boundaries. Discovery of botanical KCNQ5-selective potassium channel openers may enable future targeted therapies for diseases including hypertension and KCNQ5 loss-of-function encephalopathy.

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“…The incidence of KCNQ2-E is reported to be 1-3/100.000 births (Lopez-Rivera et al, 2020). By contrast, only a handful of DEE patients with pathogenic variants in KCNQ3 or KCNQ5 have been described (Rauch et al, 2012;Epi4k Consortium et al, 2013;Lehman et al, 2017;Ambrosino et al, 2018;Kothur et al, 2018;Lauritano et al, 2019;Rosti et al, 2019;Sands et al, 2019).…”

Section: Human Pathogenic Kcnq2 Variants and Neurodevelopmentmentioning

confidence: 99%

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

et al. 2020

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Kv7.2 subunits encoded by the KCNQ2 gene constitute a critical molecular component of the M-current, a subthreshold voltage-gated potassium current controlling neuronal excitability by dampening repetitive action potential firing. Pathogenic loss-of-function variants in KCNQ2 have been linked to epilepsy since 1998, and there is ample functional evidence showing that dysfunction of the channel indeed results in neuronal hyperexcitability. The recent description of individuals with severe developmental delay with or without seizures due to pathogenic variants in KCNQ2 (KCNQ2-encephalopathy) reveals that Kv7.2 channels also have an important role in neurodevelopment. Kv7.2 channels are expressed already very early in the developing brain when key developmental processes such as proliferation, differentiation, and synaptogenesis play a crucial role in brain morphogenesis and maturation. In this review, we will discuss the available evidence for a role of Kv7.2 channels in these neurodevelopmental processes, focusing in particular on insights derived from KCNQ2related human phenotypes, from the spatio-temporal expression of Kv7.2 and other Kv7 family member, and from cellular and rodent models, highlighting critical gaps and research strategies to be implemented in the future. Lastly, we propose a model which divides the M-current activity in three different developmental stages, correlating with the cell characteristics during these particular periods in neuronal development, and how this can be linked with KCNQ2-related disorders. Understanding these mechanisms can create opportunities for new targeted therapies for KCNQ2-encephalopathy.

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Intragenic duplication of KCNQ5 gene results in aberrant splicing leading to a premature termination codon in a patient with intellectual disability

Cited by 18 publications

References 18 publications

Loss-of-function variants in the KCNQ5 gene are associated with genetic generalized epilepsies

Loss-of-function variants in the KCNQ5 gene are associated with genetic generalized epilepsies

KCNQ5 activation is a unifying molecular mechanism shared by genetically and culturally diverse botanical hypotensive folk medicines

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding

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