Debbie Chen Abstracts

Debbie Chen Abstracts

 

Debbie Chen 
Ph.D. Student
Cancer Biology GIDP

 American Society of Human Genetics Annual Meeting
 Baltimore, Maryland
 October 6-10, 2015

Professional Abstract

Lay Audience Abstract

Characterization of SCN8A mutations and phenotypes in comparison to SCN1A

Authors:
-Debbie Chen

Graduate Interdisciplinary Program in Genetics, University of Arizona, Tucson, Arizona, USA
debbiechen@email.arizona.edu(link sends e-mail)
-Atsushi Ishii
Department of Pediatrics, Fukuoka University School of Medicine, Fukuoka, Japan University of Arizona Genomics Core, University of Arizona, Tucson, Arizona, USA
ishii@fukuoka­u.ac.jp(link sends e-mail)-Michael Hammer
Arizona Research Laboratories, Division of Biotechnology, University of Arizona, Tucson, Arizona, USA
mfh@email.arizona.edu(link sends e-mail)

Abstract:

SCN8A, a voltage­gated sodium ion channel, is a large protein (260 kDa) with four repeats. Each of these repeats has six transmembrane domains with connecting loops in between them. It is in the same gene family as SCN1A, a causal gene of Dravet Syndrome (DS), a severe, infantile epilepsy. SCN1A and SCN8A are highly conserved and have high homology. Knockouts in SCN8A cause ataxic phenotypes in mice and have only recently been shown to cause seizures and major neurodevelopmental delay in humans. Since then, 42 additional pathogenic mutations have been reported. On the other hand, more than a thousand mutations in SCN1A have been reported and well studied, with phenotypes characterized by febrile seizures. Using what we know about SCN1A, we aim to characterize SCN8A mutations and their corresponding phenotypes and ultimately discover patterns that may be used to predict pathogenicity of new mutations. We will be using the 43 SCN8A mutations published in the literature as well as a sample of 270 Dravet patients with thorough genetic and phenotypic data.

In SCN8A, we have 38 (88%) mutations that are de novo, 2 (5%) inherited, and 2 (5%) with unknown inheritance patterns. All mutations are missense except for one nonsense mutation. Interestingly, the patient presented with ataxia, not epilepsy. In comparison, more than a half of the mutations in SCN1A are truncation mutations (151/270, 56%) and result in a more severe phenotype.

21 SCN8A mutations appear in transmembrane domains while 22 appear in the loops. Despite the loops being nearly three times longer than the transmembrane domains, mutations are significantly more likely to appear in transmembrane domains than the loops in between (Fisher’s Exact Test, two­sided p­value=0.0034). This may be because mutations in loops result in a milder phenotype and may be subclinical. SCN1A mutations do not have the same significance (Fisher’s Exact Test, two­sided p­value=0.3829).

We hope to increase our sample size over the next few years as more mutations are reported. We are also establishing a framework to crowdsource patient data by creating an online presence where parents of children with SCN8A mutations can contact researchers and each other for information. Although not ready to publish, we have already collected 33 responses. Future plans also include studying mouse models with different SCN8A mutations.

Abstract for Lay Audience

The brain is a complex organ with many parts and players. Most of it is made up of specialized cells called neurons. The neurons have proteins, called sodium ion channels, that let sodium ions in and out of the cell and affect the cell’s behavior. One special class of sodium ion channels, called voltage­gated sodium ion channels, reacts to the voltage, or difference in charge across the neuron’s membrane, in deciding whether to open or close. The genes that encode these proteins are in the SCN family and their DNA sequences are very similar to each other. The main, alpha subunit of these proteins is large and loops in and out of the neuron through the membrane.

One member of the family, SCN1A, is well­studied because mutations in that gene can often lead to Dravet Syndrome, a severe type of epilepsy that begins in infancy. Another member of the family, SCN8A, also causes severe epilepsy in infants, but is not as well­studied. As mutations in other members of the SCN gene family do not cause epilepsy, we will use what we know about SCN1A to help study SCN8A.

Previously, SCN8A studies involved using mouse models to observe what happens to them if one of their two copies of SCN8A was knocked out. Interestingly, instead of seizures, the mice had ataxia, or difficulty in controlling their body movements suggesting a different mechanism or pathway compared to humans. In human patients, seizures appear when the patients have any of the currently 43 known SCN8A mutations. Compare this to the more than a thousand known mutations in SCN1A. To bridge this knowledge gap, we aim to use a Japanese cohort of 270 Dravet Syndrome patients and their respective medical history to characterize the SCN8A mutations, their phenotypes, and ultimately draw patterns and conclusions that may be used to inform clinicians and researchers about new mutations.

The main difference between SCN1A and SCN8A mutations is that there is only one reported stop­gain mutation for SCN8A while the rest are missense. Comparatively in SCN1A, more than half of the mutations are stop­gain with the other half as missense. The patient with the stop­gain mutation in SCN8A had ataxia instead of epilepsy, suggesting a milder outcome. On the other hand, patients with stop­gain mutations in SCN1A have more severe outcomes than patients with missense mutations. SCN8A mutations are also more likely to appear in the sections of protein that run through the neuron’s membrane, even after correcting for the fact that these sections are three times shorter than the connecting regions (Fisher’s Exact Test, two­sided p­value=0.0034). SCN1A mutations do not have such a difference in where mutations appear (Fisher’s Exact Test, two­sided p­value=0.3829).

Because the sample size of SCN8A mutations is so small, we hope to collect more mutations as more papers are reported. We are also creating a network for families of patients with SCN8A mutations to share their mutations and experiences with other families and researchers. Currently, 33 families have joined this network. Using this newfound information from human patients, we also hope to rapidly expand the study of new SCN8A mutations using mouse models.