Dataset Information

Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.

ABSTRACT:

Background

Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood.

Methods

This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies.

Results

We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation.

Conclusions

This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.

SUBMITTER: Cousin MA

PROVIDER: S-EPMC9195326 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.

Cousin Margot A MA Veale Emma L EL Dsouza Nikita R NR Tripathi Swarnendu S Holden Robyn G RG Arelin Maria M Beek Geoffrey G Bekheirnia Mir Reza MR Beygo Jasmin J Bhambhani Vikas V Bialer Martin M Bigoni Stefania S Boelman Cyrus C Carmichael Jenny J Courtin Thomas T Cogne Benjamin B Dabaj Ivana I Doummar Diane D Fazilleau Laura L Ferlini Alessandra A Gavrilova Ralitza H RH Graham John M JM Haack Tobias B TB Juusola Jane J Kant Sarina G SG Kayani Saima S Keren Boris B Ketteler Petra P Klöckner Chiara C Koopmann Tamara T TT Kruisselbrink Teresa M TM Kuechler Alma A Lambert Laëtitia L Latypova Xénia X Lebel Robert Roger RR Leduc Magalie S MS Leonardi Emanuela E Lewis Andrea M AM Liew Wendy W Machol Keren K Mardini Samir S McWalter Kirsty K Mignot Cyril C McLaughlin Julie J Murgia Alessandra A Narayanan Vinodh V Nava Caroline C Neuser Sonja S Nizon Mathilde M Ognibene Davide D Park Joohyun J Platzer Konrad K Poirsier Céline C Radtke Maximilian M Ramsey Keri K Runke Cassandra K CK Guillen Sacoto Maria J MJ Scaglia Fernando F Shinawi Marwan M Spranger Stephanie S Tan Ee Shien ES Taylor John J Trentesaux Anne-Sophie AS Vairo Filippo F Willaert Rebecca R Zadeh Neda N Urrutia Raul R Babovic-Vuksanovic Dusica D Zimmermann Michael T MT Mathie Alistair A Klee Eric W EW

Genome medicine 20220613 1

<h4>Background</h4>Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood.<h4>Methods</h4>This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 ...[more]

PMID: 35698242

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Project description:T-type calcium channels (Cav3.1 to Cav3.3) regulate low-threshold calcium spikes, burst firing and rhythmic oscillations of neurons and are involved in sensory processing, sleep, and hormone and neurotransmitter release. Here, we examined four heterozygous missense variants in CACNA1I, encoding the Cav3.3 channel, in patients with variable neurodevelopmental phenotypes. The p.(Ile860Met) variant, affecting a residue in the putative channel gate at the cytoplasmic end of the IIS6 segment, was identified in three family members with variable cognitive impairment. The de novo p.(Ile860Asn) variant, changing the same amino acid residue, was detected in a patient with severe developmental delay and seizures. In two additional individuals with global developmental delay, hypotonia, and epilepsy, the variants p.(Ile1306Thr) and p.(Met1425Ile), substituting residues at the cytoplasmic ends of IIIS5 and IIIS6, respectively, were found. Because structure modelling indicated that the amino acid substitutions differentially affect the mobility of the channel gate, we analysed possible effects on Cav3.3 channel function using patch-clamp analysis in HEK293T cells. The mutations resulted in slowed kinetics of current activation, inactivation, and deactivation, and in hyperpolarizing shifts of the voltage-dependence of activation and inactivation, with Cav3.3-I860N showing the strongest and Cav3.3-I860M the weakest effect. Structure modelling suggests that by introducing stabilizing hydrogen bonds the mutations slow the kinetics of the channel gate and cause the gain-of-function effect in Cav3.3 channels. The gating defects left-shifted and increased the window currents, resulting in increased calcium influx during repetitive action potentials and even at resting membrane potentials. Thus, calcium toxicity in neurons expressing the Cav3.3 variants is one likely cause of the neurodevelopmental phenotype. Computer modelling of thalamic reticular nuclei neurons indicated that the altered gating properties of the Cav3.3 disease variants lower the threshold and increase the duration and frequency of action potential firing. Expressing the Cav3.3-I860N/M mutants in mouse chromaffin cells shifted the mode of firing from low-threshold spikes and rebound burst firing with wild-type Cav3.3 to slow oscillations with Cav3.3-I860N and an intermediate firing mode with Cav3.3-I860M, respectively. Such neuronal hyper-excitability could explain seizures in the patient with the p.(Ile860Asn) mutation. Thus, our study implicates CACNA1I gain-of-function mutations in neurodevelopmental disorders, with a phenotypic spectrum ranging from borderline intellectual functioning to a severe neurodevelopmental disorder with epilepsy.

Dataset Information

Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.

Background

Methods

Results

Conclusions

Publications

Gain and loss of TASK3 channel function and its regulation by novel variation cause KCNK9 imprinting syndrome.

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