Maternally Inherited Birk Barel Mental Retardation Dysmorphism Syndrome Caused by a Mutation in the Genomically Imprinted Potassium Channel KCNK9

Barel, Ortal; Shalev, Stavit A.; Ofir, Rivka; Golan‐Cohen, Avivit; Zlotogora, Joël; Shorer, Zamir; Mazor, Galia; Finer, Gal; Khateeb, Shareef; Zilberberg, Noam; Birk, Ohad S.

doi:10.1016/j.ajhg.2008.07.010

Cited by 150 publications

(131 citation statements)

References 26 publications

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“…1). This is also in contrast with results obtained for the same mutation expressed in oocytes by Barel et al (2008), who described the TASK3_G236R mutant as nonfunctional. Unlike WT TASK3 channel current, which is outwardly rectifying (Fig.…”

Section: Resultscontrasting

confidence: 55%

“…A point mutation of G236 to an R in TASK3 is found in patients suffering from Birk Barel mental retardation dysmorphism syndrome (Barel et al, 2008). In this study, we show that TASK3_G236R does, in fact, give rise to a functional current, albeit with much smaller currents in an outward direction.…”

Section: Discussionmentioning

confidence: 60%

“…Indeed, a mutation in TASK3 (G236R) is responsible for Birk Barel mental retardation dysmorphism syndrome, a maternally transmitted developmental disorder (Barel et al, 2008). It has been proposed that the migration defect caused by dysfunctional TASK3 channels in cortical pyramidal neurons may contribute to the resulting developmental disorders (Bando et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

et al. 2013

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TASK3 (TWIK-related acid-sensitive K 1 channel 3) potassium channels are members of the two-pore-domain potassium channel family. They are responsible for background leak potassium currents found in many cell types. TASK3 channels are genetically imprinted, and a mutation in TASK3 (G236R) is responsible for Birk Barel mental retardation dysmorphism syndrome, a maternally transmitted developmental disorder. This syndrome may arise from a neuronal migration defect during development caused by dysfunctional TASK3 channels. Through the use of whole-cell electrophysiologic recordings, we have found that, although G236R mutated TASK3 channels give rise to a functional current, this current is significantly smaller in an outward direction when compared with wild-type (WT) TASK3 channels. In contrast to WT TASK3 channels, the current is inwardly rectifying. Furthermore, the current through mutated channels is differentially sensitive to a number of regulators, such as extracellular acidification, extracellular zinc, and activation of Gaq-coupled muscarinic (M3) receptors, compared with WT TASK3 channels. The reduced outward current through mutated TASK3_G236R channels can be overcome, at least in part, by both a gain-of-function additional mutation of TASK3 channels (A237T) or by application of the nonsteroidal anti-inflammatory drug flufenamic acid (FFA; 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid). FFA produces a significantly greater enhancement of current through mutated channels than through WT TASK3 channels. We propose that pharmacologic enhancement of mutated TASK3 channel current during development may, therefore, provide a potentially useful therapeutic strategy in the treatment of Birk Barel syndrome.

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Section: Resultscontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

et al. 2013

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“…The impact of genomic mutations in imprinted genes on the clinical outcome has furthermore been shown for mental retardation: maternally inherited KCNK9 mutations have been identified to cause the Birk-Barel mental retardation syndrome [9].…”

Section: Mmentioning

confidence: 99%

Congenital imprinting disorders: Application of multilocus and high throughput methods to decipher new pathomechanisms and improve their management

Soellner

Monk

Rezwan

et al. 2015

Molecular and Cellular Probes

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Imprinting disorders (IDs) are a group of congenital diseases affecting growth, development and metabolism. They are caused by changes in the allele-specific regulation ("epigenetic mutation") or in the genomic sequence ("genetic mutation") of imprinted genes. Currently molecular tests in ID patients are generally restricted to single loci classically associated with the disease, but this approach limits diagnostic yield, because of the molecular and clinical heterogeneity between IDs. From the technical point of view, these limitations are aggravated by the lack of standardization in testing methodology, in the DNA sequences tested, and in clinical inclusion criteria prompting testing.However, an increasing number of new studies show that these problems can be addressed by the use of new tests targeting multiple loci and/or a total exome and genome analysis.The rapid development of efficient and high-throughput molecular techniques and their applications in research and diagnostics in the last decade have led to an impressive increase of knowledge on IDs and their basic pathomechanisms. In combination with the improvement of data recording and documentation, the diagnostic strategies are increasingly based on standardized protocols, and thereby provide the backbone for directed counselling, more personalized management, and new therapeutic approaches.

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“…Examples are TASK subfamily K 2P channels TASK-1 (K 2P 3.1) and TASK-3 (K 2P 9.1), which are exquisitely sensitive to extracellular proton concentration (8 -11). TASK-3 is fundamental to various cellular functions including the modulation of sleep (12), aldosterone/renin secretion (13,14), and O 2 sensing (15), and its dysfunction has been linked to the Birk Barel mental retardation dysmorphism syndrome (16). TASK-3 is inactive (closed) at acid extracellular pH (pH o ) but activates (opens) as pH o is increased.…”

mentioning

confidence: 99%

An Extracellular Ion Pathway Plays a Central Role in the Cooperative Gating of a K2P K+ Channel by Extracellular pH*

González

Zúñiga

Cid

et al. 2013

Journal of Biological Chemistry

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Maternally Inherited Birk Barel Mental Retardation Dysmorphism Syndrome Caused by a Mutation in the Genomically Imprinted Potassium Channel KCNK9

Cited by 150 publications

References 26 publications

Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

Recovery of Current through Mutated TASK3 Potassium Channels Underlying Birk Barel Syndrome

Congenital imprinting disorders: Application of multilocus and high throughput methods to decipher new pathomechanisms and improve their management

An Extracellular Ion Pathway Plays a Central Role in the Cooperative Gating of a K2P K+ Channel by Extracellular pH*

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