Mysteries of the cytoskeleton – SPTAN1 in epileptic encephalopathies

Neuronal spectrinopathies. Spectrins are a major component of the neuronal cytoskeleton, the scaffold underneath the cell membrane that gives cells their characteristic shape and anchors transmembrane proteins such as voltage-gated ion channels. SPTAN1, the gene coding for the non-erythrocyte alpha-II spectrin, has been known as a rare cause of early-onset epileptic encephalopathies with hypomyelination and atrophy. However, the full phenotypic spectrum and the range of pathogenic variants was unknown. In a recent publication in Brain, 20 patients with pathogenic variants in SPTAN1 are reported, expanding the known range of phenotypes and suggesting a very unusual disease mechanism through in-frame deletions or duplications. Here is what links the neuronal cytoskeleton to epileptic encephalopathies. Continue reading

The OMIM epileptic encephalopathy genes – a 2014 review

EIEE1-19. Online Mendelian Inheritance in Man (OMIM) is one of the most frequently accessed online databases for information on genetic disorders. Genes for epileptic encephalopathies are organized within a phenotypic series entitled Early Infantile Epileptic Encephalopathy (EIEE). The EIEE phenotypic series currently lists 19 genes (EIEE1-19). Let’s review the evidence for these genes as of 2014. Continue reading

Mutation intolerance – why some genes withstand mutations and others don’t

The river of genetic variants. The era of high-throughput sequencing has given us several unexpected insights into the human genome. One of these insights is the observation that mutations or variations can occur in parts of our genome without any major consequences. Every individual is a “knockout” for at least two genes in the human genome. This means that in every individual, both copies of a single gene are disrupted through mutations or small deletions or duplications. In addition, there are dozens, if not hundreds, of genes with disruptive mutations that affect only a single copy of the gene. Similar mutations in specific disease-associated genes, however, will invariably result in an early onset genetic disorder. This comparison already shows that the genes in the human genome differ with respect to the amount of disruptive genetic variation they can tolerate. A recent study in PLOS Genetics now tries to catalogue the genes in the human genome by assessing their mutation intolerance based on the genetic variation seen in large-scale exome datasets. Many genes for neurodevelopmental disorders are highly intolerant to mutations. Furthermore, some genes for monogenic epilepsies show surprising results in this assessment. Continue reading

De novo mutations in Infantile Spasms and Lennox-Gastaut Syndrome

Quantum leap. At the Annual Meeting of the American Epilepsy Society, the Epi4K consortium presented the first data on exome sequencing in epileptic encephalopathies. This data is the most exciting finding in the field of epilepsy genetics in 2012 so far, as it provides a deep insight into the genetic architecture of Infantile Spasms (IS) and Lennox-Gastaut Syndrome (LGS). With the findings presented by the Epi4K collaborators, the epileptic encephalopathies are joining a group of neurodevelopmental disorders with a significant burden of de novo mutations.  However, there are important differences that set both IS and LGS apart from diseases like autism, intellectual disability and schizophrenia. Continue reading

Old friends

The functional interactions of two genes can be predicted by their conserved proximity in the genomes of distant species. The observation can be used to build large scale networks for bacterial species e.g. in the STRING database but there is little evidence for such conservation in larger eukaryotic species such as animals. Metazoan gene order is scrambled after short periods of evolutionary time and few interactions can be found except for the conserved Hox gene clusters.

Gene-gene pairs in metazoan genomes. Irimia et al. now show the prediction of 600 gene-gene interactions in human and more in other species by analysis of conservation across 17 metazoan genomes and demonstrate the validity by a variety of large scale experiments. In brief, some gene-gene-pairs are more conserved than expected, suggesting a functional relationship. Not all gene pairs are adjacent – longer range interactions are also studied.  It’s funny to read such a seemingly simple analysis in 2012 as so many people will have tried similar lines of research after the observations by Abachi and Lieber about bidirectional promoters, i.e. promotors, which affect gene expression in the upstream and downstream direction. The small number of available metazoan genomes might have been a cause for the late discovery. Or am I expecting science to move too fast?

Adachi and Lieber found that bi-directional gene pairs are conserved in higher eukaryotes and suggest the accepted explanation that a single promoter drives the expression of both genes.

Location, location, location. The number of new interactions identified by Irimia et al. is small but the experimental data lined up supposedly point towards high degree of true positives. The identified genes might not be of direct interest to epilepsy genetics as they are primarily found it basic cellular functions. But the observation that conservation is strong on a few gene pairs hopefully allows a glimpse on what shapes the genetic architecture, suggesting other neighbouring genes in humans might have positional effects. A recent publication by Campbell et al. provides an interesting example for epilepsy research and suggests cis-regulatory effects between epilepsy genes at the chromosomal region 9q34 including STXBP1 and SPTAN1. I wonder what role non-coding RNAs play in the cases presented by Irimia et al., which is not touched upon.