Author Archives: Roland Krause

Mutations in the same residue and phenotypic consequences in SCN1A

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The link between a mutation and the corresponding phenotype in genetic epilepsies is sometimes not trivial. Mutations in the same gene can lead to different phenotypes (phenotypic heterogeneity) and different genes can lead to the same phenotype (genetic heterogeneity). These issues appear to be particularly prominent in some forms of seizure disorders. One of the many active research fields in genetics is studying whether environmental factors or other mutations lead to the development of a given syndrome.

Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) can be due to the mutations in the same residue of the alpha-subunit of a voltage gated sodium channel encoded by SCN1A. Japanese researches now report in Epilepsia that the interaction with the beta-subunit of the channel rescues the GEFS+ associated mutant A1685V but not A1685D considered to be responsible for SMEI.

It’s a small step up on our understanding of such mutants. Computational analysis suggests that both variants have strong effects. E.g. Polyphen-2 predicts both to be probably damaging. It will still require further research on interactions to assess the differences. Part of this research is carried out in EuroEPINOMICS projects.

Exome sequencing for neurological syndromes

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Model of SCN2A protein from Modbase. Its lower half is the membrane region, which can be seen in the distribution of carbon (white).

SNC2A plays a significant role in autism reported one of three recent exome sequencing studies [1].  We were enthusiastic but others – Mike Eisen in particularly – were critical about the claim. Statistically, his analysis is correct but there is context around SCN2A that should be considered. First, it was already shown to be implicated as early as 2003[2]. The new study reconfirms the finding and provides new evidence corroborating the previous results. Soft factors, particular its known expression in the brain and its role in epilepsy would possibly make it an interesting finding even if it would have been detected in a single case.

Ben Neale, the first author of one of the studies summarized the findings in a recommended blog post. Complex diseases are complex. If years and years of research found a syndrome to be influenced by many factors, is hard to characterize, no sequencing effort no matter how deep find a simple mutation explaining most of the cases – or even a sizable part.

Some of the experiments performed in the EuroEPINOMICS consortium are close in design to the three autism studies. They should provide us with expectations and update us on experimental standards and statistical standards. And teach us some modesty.