A novel autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel gating activation, deactivation and inactivation

KCNB1, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human KCNB1 mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C>A, p. (S114R) in KCNB1, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings' father demonstrated autistic features and was determined to be an obligate KCNB1 c. 342 C>A carrier based on familial genetic testing results. Functional investigation of Kv2.1-S114R using cellular electrophysiology revealed slowing of channel act..., Human genome sequencingWe received a signed case report consent form from the legal guardian of the children. Both siblings had whole exome sequencing performed at GeneDx (Gaithersburg, MD, USA) using paired-end reads on an Illumina platform. Sequence reads were aligned to human genome build GRcH37/USCS hg19. Data was filtered using GeneDx’s custom analysis tool (XomeAnalyzer). The variant was reported as a variant of uncertain significance in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria based on transcript NM_004975.2 17.
Preparation of channel subunit cRNA preparation and Xenopus laevis oocyte injectioncDNA encoding human KCNB1 was sub-cloned into a Xenopus expression vector (pMAX) incorporating Xenopus laevis β-globin 5’ and 3’ UTRs flanking the coding region to enhance translation and cRNA stability by Genscript (Piscataway, NJ, USA). The mutant KCNB1 construct was generated by Genscript and subcloned into pMAX as above. cRNA transcripts were..., , # A novel autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel gating activation, deactivation and inactivation

The datasets included are the original Excel files used to generate each panel for figures 2-4 in this manuscript. The title of each Excel file is labeled to directly correspond to the figure in the manuscript:

Figure Number & panel > Channel Investigated > Parameter Measured

The types of files included within this repository are as follows:

## IV
These data were used to generate current-voltage relationships for WT Kv2.1, Kv2.1-S114R, and Kv2.1/Kv2.1-S144R. Data in these files were measured from the peak of the prepulse current.

## Gmax
These data were used to generate conductance-voltage curves for WT Kv2.1, Kv2.1-S114R, and Kv2.1/Kv2.1-S144R. Graphs were generated by taking measurements from the tail current (-40 mV) immediately following the prepulse current.

## Erev
These data were used to estimate the reversal potential for WT Kv2.1...