Dataset Information

Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome.

ABSTRACT: Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function.

SUBMITTER: Lazo PA

PROVIDER: S-EPMC7352878 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome.

Lazo Pedro A PA García Juan L JL Gómez-Puertas Paulino P Marcos-Alcalde Íñigo Í Arjona Cesar C Villarroel Alvaro A González-Sarmiento Rogelio R Fons Carmen C

International journal of molecular sciences 20200623 12

Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous ...[more]

PMID: 32585800

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Project description:A 6-year-old boy, second son of healthy parents affected with epileptic encephalopathy of neonatal onset. Pregnancy with gestational diabetes controlled with diet. Delivery was uneventful. Since 48 hours of life, he presented episodes of cyanosis, generalized hypertonia, and tonic asymmetric postures followed by apnea. Video-EEG at 5 days of life showed bilateral and asynchronous spike-and-wave. Seizures were refractory to phenobarbital but were controlled with phenytoin. Since 3 months of age, he presented with startle episodes without EEG correlate related to the wake and sleep transition together with dystonic postures. One month later, epileptic spasms without hypsarrhythmia were observed. No response to levetiracetam and valproic acid but stopped after lacosamide (LCS) treatment was initiated (11 months of age). Metabolic tests (including CSF studies), karyotype, and brain MRI were normal. Epileptic encephalopathy gene panel was negative including hyperekplexia related genes. Progressive increase of TSH was treated with oral L-t4. At 20 months he presented recurrence of spasms that were controlled with LCS dose adjustment. V-EEG: abnormal background activity and paroxysmal multifocal discharges that showed activation and generalization during sleep. After several years of good seizure control, LCS was discontinued. He suffered from decompensation of seizures with febrile viral infection and at 5 years of age he presented startle episodes associated to auditory stimulus without EEG correlate, but during sleep, he presented epileptic spasms with EEG correlate. Treatment with vigabatrine was initiated with a clinical and EEG improvement. At physical exam he presents severe axial hypotonia without head control. Hypertonia of 4 limbs with dystonic movements of upper limbs. No hand use and is not able to sit or crawl. No development of expressive language.GMFCS: V. No development of expressive language. Last v-EEG monitoring showed bilateral polyspike discharges and clinical spasms in polygraph recording without any clear EEG correlate. Whole exome sequencing was performed and partial exon 7 duplication, heterozygous variant, in KCNQ2 was found. aCGH study detected several CNV in genes associated to neural functions (losses: LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3. Gains : PCDH19, TENM1, EFNA5).

Project description:Pathogenic variants in KCNQ2 encoding for Kv7.2 potassium channel subunits have been found in patients affected by widely diverging epileptic phenotypes, ranging from Self-Limiting Familial Neonatal Epilepsy (SLFNE) to severe Developmental and Epileptic Encephalopathy (DEE). Thus, understanding the pathogenic molecular mechanisms of KCNQ2 variants and their correlation with clinical phenotypes has a relevant impact on the clinical management of these patients. In the present study, the genetic, biochemical, and functional effects prompted by two variants, each found in a non-familial SLNE or a DEE patient but both affecting nucleotides at the KCNQ2 intron 6-exon 7 boundary, have been investigated to test whether and how they affected the splicing process and to clarify whether such mechanism might play a pathogenetic role in these patients. Analysis of KCNQ2 mRNA splicing in patient-derived lymphoblasts revealed that the SLNE-causing intronic variant (c.928-1G > C) impeded the use of the natural splice site, but lead to a 10-aa Kv7.2 in frame deletion (Kv7.2 p.G310Δ10); by contrast, the DEE-causing exonic variant (c.928G > A) only had subtle effects on the splicing process at this site, thus leading to the synthesis of a full-length subunit carrying the G310S missense variant (Kv7.2 p.G310S). Patch-clamp recordings in transiently-transfected CHO cells and primary neurons revealed that both variants fully impeded Kv7.2 channel function, and exerted strong dominant-negative effects when co-expressed with Kv7.2 and/or Kv7.3 subunits. Notably, Kv7.2 p.G310S, but not Kv7.2 p.G310Δ10, currents were recovered upon overexpression of the PIP2-synthesizing enzyme PIP5K, and/or CaM; moreover, currents from heteromeric Kv7.2/Kv7.3 channels incorporating either Kv7.2 mutant subunits were differentially regulated by changes in PIP2 availability, with Kv7.2/Kv7.2 G310S/Kv7.3 currents showing a greater sensitivity to PIP2 depletion when compared to those from Kv7.2/Kv7.2 G310Δ10/Kv7.3 channels. Altogether, these results suggest that the two variants investigated differentially affected the splicing process at the intron 6-exon 7 boundary, and led to the synthesis of Kv7.2 subunits showing a differential sensitivity to PIP2 and CaM regulation; more studies are needed to clarify how such different functional properties contribute to the widely-divergent clinical phenotypes.

Dataset Information

Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome.

Publications

Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome.

Similar Datasets

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